Staging page

Section editor transclusions Are you looking for a regimen, such as CHOP, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it! For pediatric regimens, please visit the pediatric NHL page.

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Guidelines

BSH

• 2020: McKay et al. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper

ESMO

• 2015: Tilly et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) PubMed

NCCN

• NCCN Guidelines - B-cell Lymphomas
• NCCN Guidelines - Pediatric Aggressive Mature B-Cell Lymphomas

SITC

• 2020: Neelapu et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma

Untreated, pre-phase

Vincristine & Prednisone

Regimen variant #1, PO vincristine

Study	Years of enrollment	Evidence
Peyrade et al. 2016 (LYSA LNH09-7B)	2010-2011	Phase 2

Chemotherapy

• Vincristine (Oncovin) 1 mg PO once on day -7

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg PO once per day on days -7 to -4

7-day course

Subsequent treatment

• O-miniCHOP

Regimen variant #2, IV vincristine

Study	Years of enrollment	Evidence
Pfreundschuh et al. 2004 (NHL-B1)	1993-2000	Non-randomized portion of RCT
Pfreundschuh et al. 2004 (NHL-B2)	1993-2000	Non-randomized portion of RCT
Pfreundschuh et al. 2008 (RICOVER-60)	2000-2005	Non-randomized portion of RCT
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14)	2007-2009	Phase 2

Recommended in NHL-B1 and NHL-B2 "to improve the performance status of patients and to ameliorate side-effects of the first chemotherapy cycle." Mandated in RICOVER-60 and SMARTE-R-CHOP-14. Note: NHL-B1 gave the option of a 5 to 7 day course of prednisone.

Chemotherapy

• Vincristine (Oncovin) 1 mg IV once (day not specified)

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 7

7-day course

Subsequent treatment

• NHL-B1 and NHL-B2: CHOP versus CHOP-14 versus CHOEP-14 versus CHOEP-21
• RICOVER-60: CHOP-14 versus R-CHOP-14
• SMARTE-R-CHOP-14: R-CHOP-14

References

1. NHL-B1: Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains dosing details in manuscript PubMed
2. NHL-B2: Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article contains dosing details in manuscript PubMed
3. RICOVER-60: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group. 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 dosing details in manuscript PubMed NCT00052936
4. SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N; German High-Grade Non-Hodgkin Lymphoma Study Group. 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 dosing details in manuscript PubMed NCT00052936
5. LYSA LNH09-7B: Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017 Jan;4(1):e46-e55. link to original article contains dosing details in abstract PubMed NCT01195714

Untreated, randomized data

Pola-R-CHP

Pola-R-CHP: Polatuzumab, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tilly et al. 2021 (POLARIX)	2017-2019	Phase 3 (E-switch-ooc)	R-CHOP	Superior PFS PFS24: 76.7% vs 70.2% (HR 0.73, 95% CI 0.57-0.95)

Antibody-drug conjugate therapy

• Polatuzumab vedotin (Polivy) as follows:
  • Cycles 1 to 6: 1.8 mg/kg IV once on day 1

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 6: 50 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) as follows:
  • Cycles 1 to 6: 100 mg PO once per day on days 1 to 5

21-day cycle for 8 cycles

References

1. POLARIX: Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, Herbaux C, Burke JM, Matasar M, Rai S, Izutsu K, Mehta-Shah N, Oberic L, Chauchet A, Jurczak W, Song Y, Greil R, Mykhalska L, Bergua-Burgués JM, Cheung MC, Pinto A, Shin HJ, Hapgood G, Munhoz E, Abrisqueta P, Gau JP, Hirata J, Jiang Y, Yan M, Lee C, Flowers CR, Salles G. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Jan 27;386(4):351-363. Epub 2021 Dec 14. link to original article contains dosing details in manuscript PubMed NCT03274492

R-ACVBP

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Récher et al. 2011 (LNH03-2B)	2003-2008	Phase 3 (E-esc)	R-CHOP	Superior OS OS36: 92% vs 84% (HR 0.44, 95% CI 0.28-0.81)	Increased toxicity
Ketterer et al. 2013 (LNH03-1B)	2003-2008	Phase 3 (E-esc)	ACVBP	Superior PFS PFS36: 95% vs 83% (HR 0.37, 95% CI 0.15-0.89)	Similar toxicity
Le Gouill et al. 2021 (GAINED)	2012-2015	Phase 3 (C)	G-ACVBP	Did not meet primary endpoint of EFS EFS24: 57% vs 60% (HR 1.14, 95% CI 0.91-1.43)

Note: Treatment in GAINED was PET-adapted; see paper for details.

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 1200 mg/m² IV once on day 1
• Vindesine (Eldisine) 2 mg/m² IV once per day on days 1 & 5
• Bleomycin (Blenoxane) 10 units IV once per day on days 1 & 5

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

Targeted therapy

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

CNS therapy, prophylaxis

• Methotrexate (MTX) 15 mg IT on day 1

Supportive therapy

• Filgrastim (Neupogen) 300 mcg (for patients less than 75 kg) or 480 mcg (for patients greater than or equal to 75 kg) SC once per day on days 6 to 13

14-day cycle for 4 cycles

Subsequent treatment

• Methotrexate consolidation, in 4 weeks

References

1. LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains dosing details in manuscript PubMed NCT00140595
   1. Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
2. LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed NCT00140595
3. GAINED: Le Gouill S, Ghesquières H, Oberic L, Morschhauser F, Tilly H, Ribrag V, Lamy T, Thieblemont C, Maisonneuve H, Gressin R, Bouhabdallah K, Haioun C, Damaj G, Fornecker L, Bouhabdallah R, Feugier P, Sibon D, Cartron G, Bonnet C, André M, Chartier L, Ruminy P, Kraeber-Bodéré F, Bodet-Milin C, Berriolo-Riedinger A, Brière J, Jais JP, Molina TJ, Itti E, Casasnovas RO. Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA. Blood. 2021 Apr 29;137(17):2307-2320. link to original article contains dosing details in supplement PubMed NCT01659099

R-CEOP70

R-CEOP70: Rituximab, Cyclophosphamide, Epirubicin (70 mg/m² dosing), Oncovin (Vincristine), Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Xu et al. 2019 (NHL-001)	2013-2016	Phase 3 (E-switch-ic)	1. R-CEOP90	Inferior PFS24
			2. R-CHOP	Non-inferior PFS24 PFS24: 72.4% vs 72.5% (HR 1.00, 95% CI 0.72-1.37)

Note: this arm was available to patients of all ages.

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 0

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 1 to 6: 70 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 6: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 6: 60 mg/m²/day (maximum dose of 100 mg) PO on days 1 to 5

21-day cycle for 8 cycles

Subsequent treatment

• Patients with bulky disease at diagnosis or residual masses at end of treatment: IFRT

References

1. NHL-001: Xu PP, Fu D, Li JY, Hu JD, Wang X, Zhou JF, Yu H, Zhao X, Huang YH, Jiang L, Liu F, Su LP, Chen ZW, Zeng QS, Chen JP, Fang MY, Ma J, Liu T, Song YP, Yu K, Li Y, Qiu LG, Chen XQ, Gu J, Yan JS, Hou M, Huang HY, Wang L, Cheng S, Shen Y, Xiong H, Chen SJ, Zhao WL. Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial. Lancet Haematol. 2019 Jun;6(6):e328-e337. link to original article contains dosing details in abstract PubMed NCT01852435

R-CEOP90

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Xu et al. 2019 (NHL-001)	2013-2016	Phase 3 (E-esc)	1. R-CEOP70	Superior PFS24 PFS24: 89% vs 77% (HR 0.49, 95% CI 0.27-0.86)
			2. R-CHOP	Superior PFS24 PFS24: 89% vs 76% (HR 0.44, 95% CI 0.25-0.76)

Note: this arm was only available to patients aged 16-60 years.

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 0

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 1 to 6: 90 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 6: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 6: 60 mg/m²/day (maximum dose of 100 mg) PO on days 1 to 5

21-day cycle for 8 cycles

Subsequent treatment

• Patients with bulky disease at diagnosis or residual masses at end of treatment: IFRT

References

1. NHL-001: Xu PP, Fu D, Li JY, Hu JD, Wang X, Zhou JF, Yu H, Zhao X, Huang YH, Jiang L, Liu F, Su LP, Chen ZW, Zeng QS, Chen JP, Fang MY, Ma J, Liu T, Song YP, Yu K, Li Y, Qiu LG, Chen XQ, Gu J, Yan JS, Hou M, Huang HY, Wang L, Cheng S, Shen Y, Xiong H, Chen SJ, Zhao WL. Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial. Lancet Haematol. 2019 Jun;6(6):e328-e337. link to original article contains dosing details in abstract PubMed NCT01852435

R-CHOEP-14

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

Regimen variant #1, flat-dose vincristine

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Adde et al. 2006	2001-2003	Phase 2
Schmitz et al. 2012 (DSHNHL 2002-1)	2003-2009	Phase 3 (C)	R-MegaCHOEP	Did not meet primary endpoint of EFS	Decreased toxicity

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

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycles 1 to 4, 6, 8: 375 mg/m² IV once on day 0

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

14-day cycle for 8 cycles

Subsequent treatment

• "Mandatory" for patients with bulky disease (any mass greater than 7.5cm in diameter, or extranodal involvement): RT x 36 Gy

Regimen variant #2, capped vincristine, with CNS prophylaxis

Study	Years of enrollment	Evidence
Holte et al. 2012 (NLG LBC-04)	2004-2008	Phase 2

Note: Consolidative radiotherapy "given at the discretion of the individual centers (36 to 45 Gy). Indications for giving radiotherapy after the completion of chemotherapy included bulky disease (greater than or equal to 10 cm) at diagnosis, localized PET-positive residual lesions, and residual disease, not eligible for biopsy at a localized site, and potentially curable by radiotherapy."

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• ONE of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 4
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 4

14-day cycle for 8 cycles

Subsequent treatment

• CNS prophylaxis: HiDAC, then HD-MTX

References

1. Adde M, Enblad G, Hagberg H, Sundström C, Laurell A. Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14). Med Oncol. 2006;23(2):283-93. link to original article PubMed
2. DSHNHL 2002-1: Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; German High-Grade Lymphoma Study Group. 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 NCT00129090
   1. Update: Frontzek F, Ziepert M, Nickelsen M, Altmann B, Glass B, Haenel M, Truemper L, Held G, Bentz M, Borchmann P, Dreyling M, Viardot A, Kroschinsky FP, Metzner B, Staiger AM, Horn H, Ott G, Rosenwald A, Loeffler M, Lenz G, Schmitz N. Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial. Lancet Haematol. 2021 Apr;8(4):e267-e277. Epub 2021 Mar 2. link to original article PubMed
3. NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article contains dosing details in manuscript PubMed NCT01502982

R-CHOP

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
R-CHOP-21: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone given every 21 days
CHOP-R: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, Rituximab
RCHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
CHOPR: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, Rituximab

Example orders

• Example orders for R-CHOP in lymphoma

Note: most of the variation between regimen variants is in the dose of prednisone.

Regimen variant #1, prednisone 40 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Coiffier et al. 2002 (LNH 98-5)	1998-2000	Phase 3 (E-RT-esc)	CHOP	Superior OS OS24: 70% vs 57% (HR 0.64, 95% CI 0.45-0.89)
Delarue et al. 2013 (LNH03-6B)	2003-2008	Phase 3 (C)	R-CHOP-14	Did not meet primary endpoint of EFS

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Supportive therapy

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

21-day cycle for 8 cycles

CNS therapy, prophylaxis

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

• Methotrexate (MTX) 15 mg IT once on day 1

21-day cycle for 4 cycles

Regimen variant #2, prednisone 60 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Récher et al. 2011 (LNH03-2B)	2003-2008	Phase 3 (C)	R-ACVBP	Inferior OS	Decreased toxicity
Li et al. 2018 (CSWOG0001)	2008-2014	Phase 3 (C)	R-CHOP-14	Did not meet primary endpoint of DFS	Similar toxicities

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

21-day cycle for 8 cycles

Regimen variant #3, prednisone 100 mg, capped vincristine, 4 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Poeschel et al. 2019 (FLYER)	2005-2016	Phase 3 (E-de-esc)	R-CHOP x 6	Non-inferior PFS PFS36: 96% vs 93%	Less toxic

Note: Patients in FLYER were 18 to 60 and had no risk factors according to age-adjusted IPI.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 4: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) as follows:
  • Cycles 1 to 4: 100 mg IV or PO once per day on days 1 to 5

21-day cycle for 4 cycles

Regimen variant #4, prednisone 100 mg, capped vincristine, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Vose et al. 2001	NR	Phase 2
Merli et al. 2012 (ANZINTER3)	2003-2006	Phase 3 (C)	R-miniCEOP	Did not meet primary endpoint of EFS
Herbrecht et al. 2013 (PIX203)	2005-2008	Randomized Phase 2 (C)	CPOP-R	Inconclusive whether non-inferior CR/CRu rate1
Poeschel et al. 2019 (FLYER)	2005-2016	Phase 3 (C)	R-CHOP x 4	Non-inferior PFS36	More toxic
Oki et al. 2013 (MDACC 2005-0054)	2005-NR	Randomized Phase 2 (C)	R-Hyper-CVAD/R-MA	Seems to have inferior CRR
Seymour et al. 2014 (MAIN)	2007-2010	Phase 3 (C)	RA-CHOP-21	Did not meet secondary endpoint of PFS	Better cardiac safety
Leonard et al. 2017 (C05013)	2009-2013	Randomized Phase 2 (C)	VR-CHOP	Did not meet primary endpoint of PFS
Vitolo et al. 2017 (GOYA)	2011-2014	Phase 3 (C)	G-CHOP	Did not meet primary endpoint of PFS
Younes et al. 2019 (PHOENIX)	2013-2015	Phase 3 (C)	IR-CHOP	Did not meet primary endpoint of EFS
Nowakowski et al. 2021 (ROBUST)	2015-2017	Phase 3 (C)	R2-CHOP	Did not meet primary endpoint of PFS

¹While the primary endpoint in PIX203 was inconclusive (non-inferiority by CR/CRu rate), this arm seemed to have superior OS.
Note: patients in Vose et al. 2001 received rituximab 2 days before CHOP, i.e., all CHOP days are moved forward by 2 days. Patients in GOYA received 8 doses of rituximab, regardless of the number of chemotherapy cycles given. Patients in FLYER were 18 to 60 and had no risk factors according to age-adjusted IPI. Patients in ROBUST could receive two additional cycles of rituximab (8 total), per local practices.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg IV or PO once per day on days 1 to 5

Supportive therapy

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

21-day cycle for 6 to 8 cycles (see note)

Subsequent treatment

• Some protocols: Radiation therapy was scheduled for sites of previous bulky disease or partially responding sites

Regimen variant #5, prednisone 100 mg, capped vincristine, 6+2 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tilly et al. 2021 (POLARIX)	2017-2019	Phase 3 (C)	Pola-R-CHP	Inferior PFS

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 6: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 6: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) as follows:
  • Cycles 1 to 6: 100 mg PO once per day on days 1 to 5

21-day cycle for 8 cycles

Regimen variant #6, prednisone 100 mg, flat-dose vincristine

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Pfreundschuh et al. 2006 (NCIC-CTG LY.9)	2000-2003	Phase 3 (E-RT-esc)	1. CHOP 2. CHOEP-21 3. MACOP-B 4. PMitCEBO	Superior EFS1 EFS72: 74.3% vs 55.8%	Similar toxicity

¹Reported efficacy is based on the 2011 update.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• G-CSF with one of the following:
  • Filgrastim (Neupogen) used at physician discretion for neutropenia
  • Lenograstim (Granocyte) used at physician discretion for neutropenia

21-day cycle for 6 cycles

Subsequent treatment

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

Regimen variant #7, prednisone 100 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Offner et al. 2015 (LYM-2034)	2010-2011	Randomized Phase 2 (C)	VR-CAP	Did not meet primary endpoint of CR rate

=Biomarker eligibility criteria

• Non-germinal center B-cell (non-GCB) DLBCL

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 6 cycles

Regimen variant #8, rituximab lead-in

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Habermann et al. 2006 (ECOG E4494)	1998-2001	Phase 3 (E-RT-esc)	CHOP	Seems to have superior FFS

Note: an advantage for maintenance was only seen in the group receiving CHOP upfront, which is no longer standard of care.

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days -7 & -3
  • Cycle 2 onwards: 375 mg/m² IV once on day -2

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Recommended: Filgrastim (Neupogen) "according to guidelines"

21-day cycle for 6 to 8 cycles

Subsequent treatment

• Rituximab maintenance versus observation

Regimen variant #9, short-course for early stage DLBCL

Study	Years of enrollment	Evidence
Persky et al. 2008 (SWOG S0014)	2000-2002	Phase 2
Yoon et al. 2017 (CISL 12-09)	2010-2013	Phase 2

Note: CISL 12-09 does not have dosing details.

Preceding treatment

• CISL 12-09: Surgical resection

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Prephase: 375 mg/m² IV once on day -7
  • Cycles 1 to 3: 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle for 3 cycles

Subsequent treatment

• SWOG S0014: IFRT to begin 3 weeks after last cycle of R-CHOP

Regimen variant #10, primary testicular DLBCL

Study	Years of enrollment	Evidence
Vitolo et al. 2011 (IELSG-10)	2001-2006	Phase 2

This regimen is for primary testicular lymphoma, and is a component of a sequential treatment protocol.

Preceding treatment

• Diagnostic orchiectomy prior to starting chemotherapy

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 0 or 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

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

CNS therapy, prophylaxis

• Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22

4-week course

Subsequent treatment

• RT

Regimen variant #11, 2 cycles with response adaptation

Study	Years of enrollment	Evidence
Witzig et al. 2015 (ECOG E3402)	2004-2008	Phase 2

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

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 2 cycles

Subsequent treatment

• CR based on CT scan: R-CHOP x 2 (4 cycles total), then ibritumomab tiuxetan consolidation
• CRu or PR based on CT scan: R-CHOP x 4 (6 cycles total), then ibritumomab tiuxetan consolidation

References

1. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001 Jan 15;19(2):389-97. link to original article contains dosing details in manuscript PubMed
2. LNH 98-5: Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C; Groupe d'Etude des Lymphomes de l'Adulte. 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 dosing details in manuscript 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 dosing details in abstract 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 dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
   3. Update: Mounier N, Heutte N, Thieblemont C, Briere J, Gaulard P, Feugier P, Ghesquieres H, Van Den Neste E, Robu D, Tilly H, Bouabdallah R, Safar V, Coiffier B; Groupe d'Etude des Lymphomes de l'Adulte (GELA). Ten-year relative survival and causes of death in elderly patients treated with R-CHOP or CHOP in the GELA LNH-985 trial. Clin Lymphoma Myeloma Leuk. 2012 Jun;12(3):151-4. Epub 2012 Feb 1. link to original article PubMed
3. NCIC-CTG LY.9: Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article contains dosing details in manuscript PubMed NCT00064116
   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 dosing details in abstract PubMed
4. ECOG E4494: 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 dosing details in manuscript PubMed NCT00003150
5. SWOG S0014: Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, Rimsza LM, Fisher RI, Miller TP; SWOG. 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 dosing details in manuscript PubMed
6. IELSG-10: Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Lopez-Guillermo A, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011 Jul 10;29(20):2766-72. Epub 2011 Jun 6. link to original article contains dosing details in manuscript PubMed NCT00210379
7. ANZINTER3: Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012 Apr;53(4):581-8. Epub 2011 Nov 15. link to original article contains dosing details in manuscript PubMed NCT01148446
8. LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains dosing details in manuscript PubMed NCT00140595
   1. Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
9. LNH03-6B: Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):525-33. Epub 2013 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00144755
10. PIX203: Herbrecht R, Cernohous P, Engert A, Le Gouill S, Macdonald D, Machida C, Myint H, Saleh A, Singer J, Wilhelm M, van der Jagt R. Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma. Ann Oncol. 2013 Oct;24(10):2618-23. Epub 2013 Aug 14. link to original article contains dosing details in supplement PubMed NCT00268853
11. MDACC 2005-0054: Oki Y, Westin JR, Vega F, Chuang H, Fowler N, Neelapu S, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale M, Younes A, Rodriguez MA, Orlowski RZ, Wang M, Ouzounian ST, Samaniego F, Fayad L. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013 Dec;163(5):611-20. Epub 2013 Oct 1. link to original article contains dosing details in manuscript link to PMC article contains dosing details in manuscript PubMed NCT00290498
12. SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article does not contain dosing details PubMed NCT00004031
    1. Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article PubMed
13. MAIN: Seymour JF, Pfreundschuh M, Trnený M, Sehn LH, Catalano J, Csinady E, Moore N, Coiffier B; MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica. 2014 Aug;99(8):1343-9. Epub 2014 Jun 3. link to original article link to PMC article does not contain dosing details PubMed NCT00486759
14. 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
15. ECOG E3402: Witzig TE, Hong F, Micallef IN, Gascoyne RD, Dogan A, Wagner H Jr, Kahl BS, Advani RH, Horning SJ. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015 Sep;170(5):679-86. Epub 2015 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00088881
16. LYM-2034: Offner F, Samoilova O, Osmanov E, Eom HS, Topp MS, Raposo J, Pavlov V, Ricci D, Chaturvedi S, Zhu E, van de Velde H, Enny C, Rizo A, Ferhanoglu B. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015 Oct 15;126(16):1893-901. Epub 2015 Jul 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01040871
17. CISL 12-09: Yoon DH, Sohn BS, Oh SY, Lee WS, Lee SM, Yang DH, Huh J, Suh C. Feasibility of abbreviated cycles of immunochemotherapy for completely resected limited-stage CD20+ diffuse large B-cell lymphoma (CISL 12-09). Oncotarget. 2017 Feb 21;8(8):13367-13374. link to original article link to PMC article does not contain dosing details PubMed NCT01279902
18. MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed NCT01649856
19. GOYA: Vitolo U, Trněný M, Belada D, Burke JM, Carella AM, Chua N, Abrisqueta P, Demeter J, Flinn I, Hong X, Kim WS, Pinto A, Shi YK, Tatsumi Y, Oestergaard MZ, Wenger M, Fingerle-Rowson G, Catalani O, Nielsen T, Martelli M, Sehn LH. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3529-3537. Epub 2017 Aug 10. link to original article contains dosing details in manuscript PubMed NCT01287741
    1. Update: Sehn LH, Martelli M, Trněný M, Liu W, Bolen CR, Knapp A, Sahin D, Sellam G, Vitolo U. A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA. J Hematol Oncol. 2020 Jun 6;13(1):71. link to original article link to PMC article PubMed
20. C05013: Leonard JP, Kolibaba KS, Reeves JA, Tulpule A, Flinn IW, Kolevska T, Robles R, Flowers CR, Collins R, DiBella NJ, Papish SW, Venugopal P, Horodner A, Tabatabai A, Hajdenberg J, Park J, Neuwirth R, Mulligan G, Suryanarayan K, Esseltine DL, de Vos S. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3538-3546. Epub 2017 Sep 1. link to original article contains dosing details in manuscript PubMed NCT00931918
21. CSWOG0001: Li X, Huang H, Xu B, Guo H, Lin Y, Ye S, Yi J, Li W, Wu X, Wang W, Zhan H, Xie D, Peng J, Cao Y, Pu X, Guo C, Hong H, Wang Z, Fang X, Zhou Y, Lin S, Liu Q, Lin T. Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Cancer Res Treat. 2019 Jul;51(3):919-932. Epub 2018 Oct 2. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01793844
22. PHOENIX: Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. Epub 2019 Mar 22. link to original article link to PMC article PubMed NCT01855750
23. CALGB 50303: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schöder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. Epub 2019 Apr 2. link to original article link to PMC article PubMed NCT00118209
24. FLYER: Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. link to original article contains dosing details in abstract PubMed NCT00278421
25. ROBUST: Nowakowski GS, Chiappella A, Gascoyne RD, Scott DW, Zhang Q, Jurczak W, Özcan M, Hong X, Zhu J, Jin J, Belada D, Bergua JM, Piazza F, Mócikova H, Molinari AL, Yoon DH, Cavallo F, Tani M, Yamamoto K, Izutsu K, Kato K, Czuczman M, Hersey S, Kilcoyne A, Russo J, Hudak K, Zhang J, Wade S, Witzig TE, Vitolo U. ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2021 Apr 20;39(12):1317-1328. Epub 2021 Feb 23. link to original article contains dosing details in manuscript PubMed NCT02285062
26. POLARIX: Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, Herbaux C, Burke JM, Matasar M, Rai S, Izutsu K, Mehta-Shah N, Oberic L, Chauchet A, Jurczak W, Song Y, Greil R, Mykhalska L, Bergua-Burgués JM, Cheung MC, Pinto A, Shin HJ, Hapgood G, Munhoz E, Abrisqueta P, Gau JP, Hirata J, Jiang Y, Yan M, Lee C, Flowers CR, Salles G. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Jan 27;386(4):351-363. Epub 2021 Dec 14. link to original article contains dosing details in manuscript PubMed NCT03274492
27. ESCALADE: NCT04529772
28. frontMIND: NCT04824092

R-CHOP (Prednisolone)

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

Example orders

• Example orders for R-CHOP in lymphoma

Regimen variant #1, prednisolone 40 mg/m², 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Cunningham et al. 2013 (UK NCRI R-CHOP14v21)	2005-2008	Phase 3 (C)	R-CHOP-14	Did not meet primary endpoint of OS
Fridrik et al. 2016 (AGMT NHL-14)	2007-2010	Phase 3 (C)	R-COMP	Did not meet secondary efficacy endpoints	Did not meet primary endpoint of reduced cardiotoxicity

Note: Cunningham et al. 2013 states that the regimen is based on LNH 98-5, but notably it uses prednisolone instead of prednisone. AGMT NHL-14 states that R-CHOP was "given in standard doses" per LNH 98-5, but this regimen uses prednisone, whereas the title and text of Fridrik et al. 2016 implies that prednisolone was used. The authors have confirmed that prednisolone was used, due to prednisone not being available in Austria.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) 40 mg/m² PO once per day on days 1 to 5

CNS therapy, 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 therapy

• Described in Cunningham et al. 2013
• Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12 at physician discretion
• Allopurinol (Zyloprim) 300 mg PO once per day during cycle 1
• Co-trimoxazole 80/400 mg PO twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after chemotherapy is completed

21-day cycle for 8 cycles

Regimen variant #2, prednisolone 60 mg/m², 6 + 2 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS

Note: This regimen was intended for stage I nonbulky patients who were at least 65 years old.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 6: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 6: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 6: 60 mg/m² PO once per day on days 1 to 5

21-day cycle for 8 cycles

Regimen variant #3, prednisolone 60 mg/m², 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS

Note: This regimen was intended for stage I bulky and stage II to IV patients who were at least 65 years old.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) 60 mg/m² PO once per day on days 1 to 5

21-day cycle for 8 cycles

Regimen variant #4, prednisolone 100 mg, 4 + 2 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Poeschel et al. 2019 (FLYER)	2005-2016	Phase 3 (E-de-esc)	R-CHOP x 6	Non-inferior PFS PFS36: 96% vs 93%	Less toxic

Note: Patients in FLYER were 18 to 60 and had no risk factors according to age-adjusted IPI.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 4: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 4: 100 mg IV or PO once per day on days 1 to 5

21-day cycle for 6 cycles

Regimen variant #5, prednisolone 100 mg, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Poeschel et al. 2019 (FLYER)	2005-2016	Phase 3 (C)	R-CHOP x 4	Non-inferior PFS36	More toxic
Payandeh et al. 2016	2011-2014	Phase 3 (C)	R-CHOP-14	Inferior OS
Davies et al. 2019 (REMoDL-B)	2011-2015	Phase 3 (C)	RB-CHOP	Did not meet primary endpoint of PFS30

Note: this was the lower bound of cycles specified by Payandeh et al. 2016.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

21-day cycle for 6 cycles

Regimen variant #6, prednisolone 100 mg, 6 + 2 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS

Note: This regimen was intended for stage I nonbulky patients who were younger than 65 years old.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 6: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 6: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 6: 100 mg PO once per day on days 1 to 5

21-day cycle for 8 cycles

Regimen variant #7, prednisolone 100 mg, 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS
Payandeh et al. 2016	2011-2014	Phase 3 (C)	R-CHOP-14	Inferior OS

Note: This was the upper bound of cycles specified by Payandeh et al. 2016. In JCOG0601, this regimen was intended for stage I bulky and stage II to IV patients who were younger than 65 years old.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 8 cycles

References

1. UK NCRI R-CHOP14v21: Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article contains dosing details in manuscript PubMed ISRCTN16017947
2. AGMT NHL-14: Fridrik MA, Jaeger U, Petzer A, Willenbacher W, Keil F, Lang A, Andel J, Burgstaller S, Krieger O, Oberaigner W, Sihorsch K, Greil R; Arbeitsgemeinschaft Medikamentöse Tumortherapie. 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 (NHL-14). Eur J Cancer. 2016 May;58:112-21. Epub 2016 Mar 15. link to original article does not contain dosing details PubMed NCT00575406
3. Payandeh M, Najafi S, Shojaiyan FZ, Sadeghi M. Phase III of study of R-CHOP-21 vs R-CHOP-14 for untreated stage III and IV B-cell non-Hodgkin's lymphoma: a report from Iran. Asian Pac J Cancer Prev. 2016;17(3):1513-7. link to original article contains dosing details in manuscript PubMed
4. REMoDL-B: Davies A, Cummin TE, Barrans S, Maishman T, Mamot C, Novak U, Caddy J, Stanton L, Kazmi-Stokes S, McMillan A, Fields P, Pocock C, Collins GP, Stephens R, Cucco F, Clipson A, Sha C, Tooze R, Care MA, Griffiths G, Du MQ, Westhead DR, Burton C, Johnson PWM. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019 May;20(5):649-662. Epub 2019 Apr 1. link to original article link to PMC article PubMed NCT01324596
5. FLYER: Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. link to original article contains dosing details in abstract PubMed NCT00278421
6. JCOG0601: Ohmachi K, Kinoshita T, Tobinai K, Ogawa G, Mizutani T, Yamauchi N, Fukuhara N, Uchida T, Yamamoto K, Miyazaki K, Tsukamoto N, Iida S, Utsumi T, Yoshida I, Imaizumi Y, Tokunaga T, Yoshida S, Masaki Y, Murayama T, Yakushijin Y, Suehiro Y, Nosaka K, Dobashi N, Kuroda J, Takamatsu Y, Maruyama D, Ando K, Ishizawa K, Ogura M, Yoshino T, Hotta T, Tsukasaki K, Nagai H; Japan Clinical Oncology Group. A randomized phase 2/3 study of R-CHOP vs CHOP combined with dose-dense rituximab for DLBCL: the JCOG0601 trial. Blood Adv. 2021 Feb 23;5(4):984-993. link to original article contains dosing details in manuscript PubMed jRCTs031180139

R-CHOP (Rituximab and hyaluronidase)

R-CHOP: Rituximab and hyaluronidase, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone

Example orders

• Example orders for R-CHOP in lymphoma

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lugtenburg et al. 2017 (MabEase)	2012-NR	Phase 3 (E-RT-switch-ic)	R-CHOP	Might have superior CR rate

Note: the details for CHOP are not available in the manuscript or supplement; we have reproduced common CHOP dosing, here. For patients achieving CR after cycle 4, the CHOP could be omitted after cycle 6.

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
• Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
  • Cycles 2 to 8: 1400 mg SC once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 6 to 8 cycles

References

1. MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed NCT01649856

R-CHOP-14

R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days

Synopsis

To be completed. Note that most of the variation below is in the steroid dose.

Regimen variant #1, prednisone 40 mg/m², 4 to 6 cycles

Study	Years of enrollment	Evidence
Lamy et al. 2017 (LYSA/GOELAMS 02-03)	2005-2014	Non-randomized portion of RCT

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

14-day cycle for 4 to 6 cycles

Subsequent treatment

• Observation versus IFRT x 40 Gy

Regimen variant #2, prednisone 40 mg/m², 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Delarue et al. 2013 (LNH03-6B)	2003-2008	Phase 3 (E-esc)	R-CHOP21	Did not meet primary endpoint of EFS
Le Gouill et al. 2021 (GAINED)	2012-2015	Phase 3 (C)	G-CHOP	Did not meet primary endpoint of EFS24

Note: treatment in GAINED was PET-adapted; see paper for details.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Supportive therapy

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

CNS therapy, prophylaxis

• Methotrexate (MTX) as follows:
  • Cycles 1 to 4: 15 mg IT once on day 1

14-day cycle for 8 cycles

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Cortelazzo et al. 2016	2005-2011	Phase 3 (C)	R-HDS	Did not meet primary endpoint of EFS36
Chiappella et al. 2017 (DLCL04)	2006-2010	Phase 3 (C)	1. R-MegaCHOP-14	Not reported
			2. R-CHOP-14, then R-MAD, then BEAM, then auto HSCT 3. R-MegaCHOP-14, then R-MAD, then BEAM, then auto HSCT	Did not meet primary endpoint of FFS24
Seymour et al. 2014 (MAIN)	2007-2010	Phase 3 (C)	RA-CHOP-14	Did not meet secondary endpoint of PFS	Better cardiac safety
Lugtenburg et al. 2020 (HOVON-84)	2007-2012	Phase 3 (C)	RR-CHOP-14	Did not meet primary endpoint of CR rate	Less neutropenia and infections

Note: in MAIN, CHOP-14 was given for 6 cycles and rituximab for 8 cycles. In Cortelazzo et al. 2016, there is no cap on the vincristine dose, and there is also a discrepancy between the prednisone dose in the body of the manuscript and that in the appendix Figure A1; these discrepancies were clarified by the corresponding author in January 2017. In the abstract of DLCL04, there is no cap on vincristine.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• ONE of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 11
  • Pegfilgrastim (Neulasta)

14-day cycle for 6 to 8 cycles (see note)

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pfreundschuh et al. 2014 (SEXIE-R-CHOP-14)	NR in abstract	Randomized Phase 2 (E-esc)	See below	TBD

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

Targeted therapy

• Rituximab (Rituxan) by ONE of the following schedules:
  • Cycles 1 to 8: 500 mg/m² IV once on day 1
  • 500 mg/m² IV once per day on days -1, 0, 3, 7, 14, 21, 28, 42

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

14-day cycle for 6 cycles

Regimen variant #5, prednisone 100 mg, flat dose vincristine, 2 cycles, with response adaptation

Study	Years of enrollment	Evidence
Dührsen et al. 2018 (PETAL)	2007-2012	Non-randomized portion of phase III RCT

Preceding treatment

• Vincristine & prednisone pre-phase

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 2
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 2
• Vincristine (Oncovin) 2 mg IV once on day 2

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 2 to 6

14-day cycle for 2 cycles

Subsequent treatment

• PET-negative: R-CHOP x 4 (6 cycles total) versus R-CHOP x 4, then rituximab x 2
• PET-positive: R-CHOP x 6 (8 cycles total) versus intensive Burkitt lymphoma protocol

Regimen variant #6, prednisone 100 mg, flat dose vincristine, 6 cycles, extended rituximab exposure

Study	Years of enrollment	Evidence
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14)	2007-2009	Phase 2

Preceding treatment

• Vincristine & prednisone pre-phase

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days -4, 0, 10, 29, 57, 99, 155, 239 (independent of CHOP cycles)

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• ONE of the following starting on day 4, to continue until count recovery:
  • Filgrastim (Neupogen)
  • Lenograstim (Granocyte)

14-day cycle for 6 cycles

Subsequent treatment

• Patients with initial bulky disease ("lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"): RT x 36 Gy

Regimen variant #7, prednisone 100 mg, flat dose vincristine, 6-8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pfreundschuh et al. 2008 (RICOVER-60)	2000-2005	Phase 3 (E-esc)	1. CHOP-14 x 6	Superior OS
			2. CHOP-14 x 8	Not reported
			3. R-CHOP-14 x 8	Not reported
Held et al. 2014 (RICOVER-noRTh)	2005-2007	Non-randomized portion of RCT

Preceding treatment

• RICOVER-60: Vincristine & prednisone pre-phase

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• ONE of the following starting on day 4, to continue until count recovery:
  • Filgrastim (Neupogen)
  • Lenograstim (Granocyte)

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

Subsequent treatment

• RICOVER-60: Patients with initial bulky disease ("lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"): RT x 36 Gy
• RICOVER-noRTh: RT x 36 Gy versus observation

References

1. RICOVER-60: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group. 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 dosing details in manuscript PubMed NCT00052936
2. Abstract: S. Le Gouill, N. J. Milpied, T. Lamy, V. Delwail, R. Gressin, D. Guyotat, G. L. Damaj, C. Foussard, G. Cartron, H. Maisonneuve, E. Deconinck, F. Dreyfus, E. Gyan, L. Sutton, N. Morineau, M. Alexis, F. Perry, M. Sauvezie. First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: Preliminary results of the GOELAMS 075 prospective multicenter randomized trial. Journal of Clinical Oncology 29, no. 15_suppl (May 2011) 8003-8003. link to abstract
3. LNH03-6B: Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):525-33. Epub 2013 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00144755
4. RICOVER-noRTh: Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Zwick C, Bittenbring J, Hänel M, Wilhelm S, Schubert J, Schmitz N, Löffler M, Rübe C, Pfreundschuh M. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014 Apr 10;32(11):1112-8. Epub 2014 Feb 3. link to original article PubMed NCT00052936
5. Abstract: Michael Pfreundschuh, Gerhard Held, Samira Zeynalova, Carsten Zwick, Mathias Haenel, Lorenz Truemper, Martin H. Dreyling, Judith Dierlamm, Markus Loeffler, Norbert Schmitz, Niels Murawski, German High-Grade Non-Hodgkin Lymphoma Study Group. 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 NCT00290667
6. MAIN: Seymour JF, Pfreundschuh M, Trnený M, Sehn LH, Catalano J, Csinady E, Moore N, Coiffier B; MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica. 2014 Aug;99(8):1343-9. Epub 2014 Jun 3. link to original article link to PMC article does not contain dosing details PubMed NCT00486759
7. SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N; German High-Grade Non-Hodgkin Lymphoma Study Group. 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 dosing details in manuscript PubMed NCT00052936
8. Cortelazzo S, Tarella C, Gianni AM, Ladetto M, Barbui AM, Rossi A, Gritti G, Corradini P, Di Nicola M, Patti C, Mulé A, Zanni M, Zoli V, Billio A, Piccin A, Negri G, Castellino C, Di Raimondo F, Ferreri AJ, Benedetti F, La Nasa G, Gini G, Trentin L, Frezzato M, Flenghi L, Falorio S, Chilosi M, Bruna R, Tabanelli V, Pileri S, Masciulli A, Delaini F, Boschini C, Rambaldi A. Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol. 2016 Nov 20;34(33):4015-4022. Epub 2016 Oct 31. link to original article contains dosing details in manuscript PubMed NCT00355199
9. DLCL04: Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. Epub 2017 Jun 28. link to original article contains dosing details in abstract PubMed NCT00499018
10. MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed NCT01649856
11. LYSA/GOELAMS 02-03: Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, Gressin R, Cornillon J, Banos A, Le Du K, Benchalal M, Moles MP, Le Gouill S, Fleury J, Godmer P, Maisonneuve H, Deconinck E, Houot R, Laribi K, Marolleau JP, Tournilhac O, Branger B, Devillers A, Vuillez JP, Fest T, Colombat P, Costes V, Szablewski V, Béné MC, Delwail V; LYSA. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018 Jan 11;131(2):174-181. Epub 2017 Oct 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00841945
12. PETAL: Dührsen U, Müller S, Hertenstein B, Thomssen H, Kotzerke J, Mesters R, Berdel WE, Franzius C, Kroschinsky F, Weckesser M, Kofahl-Krause D, Bengel FM, Dürig J, Matschke J, Schmitz C, Pöppel T, Ose C, Brinkmann M, La Rosée P, Freesmeyer M, Hertel A, Höffkes HG, Behringer D, Prange-Krex G, Wilop S, Krohn T, Holzinger J, Griesshammer M, Giagounidis A, Raghavachar A, Maschmeyer G, Brink I, Bernhard H, Haberkorn U, Gaska T, Kurch L, van Assema DME, Klapper W, Hoelzer D, Geworski L, Jöckel KH, Scherag A, Bockisch A, Rekowski J, Hüttmann A; PETAL Trial Investigators. Positron emission tomography-guided therapy of aggressive non-Hodgkin lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol. 2018 Jul 10;36(20):2024-2034. Epub 2018 May 11. link to original article contains dosing details in supplement PubMed NCT00554164
13. HOVON-84: Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, Fijnheer R, van Esser JW, Böhmer LH, Pruijt JF, Verhoef GE, Hoogendoorn M, Bilgin MY, Nijland M, van der Burg-de Graauw NC, Oosterveld M, Jie KG, Larsen TS, van der Poel MW, Leijs MB, Silbermann MH, van Marwijk Kooy M, Beeker A, Kersten MJ, Doorduijn JK, Tick LW, Brouwer RE, Lam KH, Burggraaff CN, de Keizer B, Arens AI, de Jong D, Hoekstra OS, Zijlstra-Baalbergen JM. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020 Oct 10;38(29):3377-3387. Epub 2020 Jul 30. link to original article contains dosing details in manuscript PubMed EudraCT 2006-005174-42
14. GAINED: Le Gouill S, Ghesquières H, Oberic L, Morschhauser F, Tilly H, Ribrag V, Lamy T, Thieblemont C, Maisonneuve H, Gressin R, Bouhabdallah K, Haioun C, Damaj G, Fornecker L, Bouhabdallah R, Feugier P, Sibon D, Cartron G, Bonnet C, André M, Chartier L, Ruminy P, Kraeber-Bodéré F, Bodet-Milin C, Berriolo-Riedinger A, Brière J, Jais JP, Molina TJ, Itti E, Casasnovas RO. Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA. Blood. 2021 Apr 29;137(17):2307-2320. link to original article contains dosing details in supplement PubMed NCT01659099

R-CHOP-14 (Prednisolone)

R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone every 14 days

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hara et al. 2018	2006-2013	Phase 3 (C)	R-THP-CHOP	Non-inferior CR rate

Note: large portions of the protocol, including the total number of cycles, are in Japanese.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 3
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 3
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 3

Glucocorticoid therapy

• Prednisolone (Millipred) 100 mg PO once per day on days 3 to 7

Supportive therapy

• Filgrastim (Neupogen) 50 mcg/kg SC once per day on days 9 to 14

14-day cycle for 6 cycles (see note)

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2013 (UK NCRI R-CHOP14v21)	2005-2008	Phase 3 (E-esc)	R-CHOP-21	Did not meet primary endpoint of OS OS24: 83% vs 81% (HR 0.90, 95% CI 0.70-1.15)

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 6: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 6: 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) as follows:
  • Cycles 1 to 6: 100 mg PO once per day on days 1 to 5

CNS therapy, 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 therapy

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

14-day cycle for 8 cycles

References

1. UK NCRI R-CHOP14v21: Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article contains dosing details in manuscript PubMed ISRCTN16017947
2. Hara T, Yoshikawa T, Goto H, Sawada M, Yamada T, Fukuno K, Kasahara S, Shibata Y, Matsumoto T, Mabuchi R, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Kanemura N, Nannya Y, Katsumura N, Takahashi T, Kito Y, Takami T, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial. Hematol Oncol. 2018 Oct;36(4):638-644. Epub 2018 Jun 8. link to original article contains dosing details in supplement PubMed UMIN000007283

R-CHOP-14 (Rituximab and hyaluronidase)

R-CHOP-14: Rituximab and hyaluronidaase, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lugtenburg et al. 2017 (MabEase)	2012-NR	Phase 3 (E-RT-switch-ic)	R-CHOP-14	Might have superior CR rate

Note: the details for CHOP-14 are not available in the manuscript or supplement; we have reproduced common CHOP-14 dosing, here. For patients achieving CR after cycle 4, the CHOP-14 could be omitted after cycle 6.

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
• Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
  • Cycles 2 to 8: 1400 mg SC once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• ONE of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 11
  • Pegfilgrastim (Neulasta)

14-day cycle for 6 to 8 cycles

References

1. MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed NCT01649856

R2-CHOP

R2-CHOP: 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 variant #1, len 15 mg/day for 14 d/cycle, pred 40 mg/m²

Study	Years of enrollment	Evidence	Efficacy
Vitolo et al. 2014 (REAL07)	2008-2009	Phase 2	ORR: 92% (95% CI 81–97)

Note: CNS prophylaxis was offered to "at risk" patients.

Targeted therapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

CNS therapy, prophylaxis

• Methotrexate (MTX) as follows:
  • Cycles 1 to 4: 12 mg IT once on day 1

Supportive therapy

• Granulocyte colony-stimulating factors (dose/duration not specified)
• Low-molecular-weight heparins (dose/duration not specified)
• PCP prophylaxis with one of the following:
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/duration not specified)
  • Pentamidine (Nebupent) (dose/duration not specified)
• Carriers of hepatitis B virus: Lamivudine (Epivir) (dose/duration not specified)

21-day cycle for 6 cycles

Regimen variant #2, len 15 mg/day for 14 d/cycle, pred 100 mg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nowakowski et al. 2021 (ROBUST)	2015-2017	Phase 3 (E-esc)	R-CHOP	Did not meet primary endpoint of PFS Median PFS: NYR vs NYR (HR 0.85, 95% CI 0.63-1.14)

Note: patients were allowed to receive to additional doses of rituximab, per local practices.

=Biomarker eligibility criteria

• ABC subtype, per NanoString Lymphoma Subtyping Test

Targeted therapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle for 6 cycles

Regimen variant #3, len 25 mg/day for 10 d/cycle

Study	Evidence	Efficacy
Nowakowski et al. 2014 (Mayo Clinic MC078E)	Phase 2	ORR: 98%

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 10
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2
• Aspirin 81 mg PO once per day unless on therapeutic dose Warfarin (Coumadin) or low molecular weight heparin

21-day cycle for up to 6 cycles

References

1. REAL07: Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G, Spina M, Pavone V, Ladetto M, Liberati AM, Molinari AL, Zinzani P, Salvi F, Fattori PP, Zaccaria A, Dreyling M, Botto B, Castellino A, Congiu A, Gaudiano M, Zanni M, Ciccone G, Gaidano G, Rossi G; 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 dosing details in manuscript PubMed NCT00907348
2. Mayo Clinic MC078E: Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, Thompson CA, Rivera CE, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Gascoyne RD, Habermann TM, Witzig TE. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol. 2015 Jan 20;33(3):251-7. Epub 2014 Aug 18. link to original article contains dosing details in manuscript PubMed NCT00670358
3. ROBUST: Nowakowski GS, Chiappella A, Gascoyne RD, Scott DW, Zhang Q, Jurczak W, Özcan M, Hong X, Zhu J, Jin J, Belada D, Bergua JM, Piazza F, Mócikova H, Molinari AL, Yoon DH, Cavallo F, Tani M, Yamamoto K, Izutsu K, Kato K, Czuczman M, Hersey S, Kilcoyne A, Russo J, Hudak K, Zhang J, Wade S, Witzig TE, Vitolo U. ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2021 Apr 20;39(12):1317-1328. Epub 2021 Feb 23. link to original article contains dosing details in manuscript PubMed NCT02285062

DA-R-EPOCH

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Wilson et al. 2008	NR	Phase 2
Wilson et al. 2011 (CALGB 50103)	2002-2004	Phase 2
García-Suárez et al. 2007	2002-2006	Phase 2
Purroy et al. 2014	2002-2008	Phase 2
Bartlett et al. 2019 (CALGB 50303)	2005-2013	Phase 3 (E-esc)	R-CHOP	Did not meet primary endpoint of PFS PFS24: 79% vs 75.5% (HR 0.93, 95% CI 0.68-1.27)	Increased toxicity

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per cycle on day -1 or 1, given before the start of EPOCH (depending on reference)

Chemotherapy

• Etoposide (Vepesid) 50 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 200 mg/m²)
• Vincristine (Oncovin) 0.4 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg/m²)
• Cyclophosphamide (Cytoxan) 750 mg/m² IV over 15 minutes once on day 5
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO twice per day on days 1 to 5

Supportive therapy

• Growth factor support with one of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6 and continuing until ANC greater than 5000/uL past nadir
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 6 (option per Purroy et al. 2014)
• PCP prophylaxis with any one of the following:
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day 3 days per week
    • Alternative used only in García-Suárez et al. 2007: cotrimoxazole 480 mg PO twice per day 3 days per week
  • Atovaquone (Mepron) 1500 mg PO once per day
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days
• Only in García-Suárez et al. 2007: Darbepoetin alfa (Aranesp) 2.25 mcg/kg SC when hemoglobin concentration was less than or equal to 10 g/dL.

21-day cycle for 6 to 8 cycles

Dose modifications

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC greater than 500/uL, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC less than 500/uL on 1 or 2 measurements, use same doses as last cycle.
• If nadir ANC less than 500/uL on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• And/or if nadir platelet count less than 25 × 10⁹/L on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at is the original cycle 1 dose.
• Can start new cycle every 21 days if ANC greater than 1000/uL and platelets greater than 100 × 10⁹/L. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

References

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 dosing details in manuscript PubMed
2. Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. link to original article link to PMC article PubMed
3. CALGB 50103: Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED; Cancer and Leukemia Group B. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012 May;97(5):758-65. Epub 2011 Dec 1. link to original article link to PMC article PubMed NCT00032019
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; PETHEMA. 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 dosing details in abstract PubMed EudraCT 2004-001684-22
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. CALGB 50303: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schöder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. Epub 2019 Apr 2. link to original article link to PMC article PubMed NCT00118209

R-Hyper-CVAD/R-MA

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

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Oki et al. 2013 (MDACC 2005-0054)	2005-NR	Randomized Phase 2 (E-esc)	R-CHOP	Seems to have increased CRR

Intended for high-risk DLBCL (IPI greater than or equal to 3). The authors report "excellent outcome" in patients less than or equal to 45 years old, however patients greater than 45 years old had "unacceptable mortality."

Targeted therapy

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

Chemotherapy, Part A (cycles 1, 3, 5)

• Cyclophosphamide (Cytoxan) 300 mg/m² IV every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 5 & 12
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 5

Glucocorticoid therapy, Part A (cycles 1, 3, 5)

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5

Supportive therapy, Part A (cycles 1, 3, 5)

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m²)
• Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) starting 24 to 48 hours after completion of chemotherapy
• Ciprofloxacin (Cipro) 500 mg PO twice per day for 10 days after chemotherapy
• Fluconazole (Diflucan) 100 mg PO once per day for 10 days after chemotherapy
• Valacyclovir (Valtrex) 500 mg PO once per day for 10 days after chemotherapy

Next cycle to start once ANC is greater than or equal to 1000/uL and platelet count is greater than or equal to 100 × 10⁹/L.

Chemotherapy, Part B (cycles 2, 4, 6)

• Methotrexate (MTX) 200 mg/m² IV over 2 hours once on day 1, then 800 mg/m² IV over 22 hours (total dose per cycle: 1000 mg/m²)
• Cytarabine (Ara-C) 3000 mg/m² IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 12,000 mg/m²)

Supportive therapy, Part B (cycles 2, 4, 6)

• Folinic acid (Leucovorin) (dose/timing not specified) until serum methotrexate level less than 100 nmol/L
• Sodium bicarbonate 1300 mg PO twice per day until methotrexate level less than 100 nmol/L
• Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) starting 24 to 48 hours after completion of chemotherapy
• Ciprofloxacin (Cipro) 500 mg PO twice per day for 10 days after chemotherapy
• Fluconazole (Diflucan) 100 mg PO once per day for 10 days after chemotherapy
• Valacyclovir (Valtrex) 500 mg PO once per day for 10 days after chemotherapy

21-day cycles

CNS therapy, 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."

Dose modifications, Part A (cycles 1, 3, 5)

• Vincristine (Oncovin) reduced once by 50% for NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted if Grade 2+ peripheral neuropathy persists
• Doxorubicin (Adriamycin) and Cyclophosphamide (Cytoxan) reduced by 20% in subsequent A cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/uL or platelet count less than 75 × 10⁹/L on day 21

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.

Dose modifications, Part B (cycles 2, 4, 6)

• Methotrexate (MTX) reduced by 25% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/uL or platelet count less than 75 × 10⁹/L on day 21
• Cytarabine (Ara-C) reduced by 33% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/uL or platelet count less than 75 × 10⁹/L on day 21

References

1. MDACC 2005-0054: Oki Y, Westin JR, Vega F, Chuang H, Fowler N, Neelapu S, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale M, Younes A, Rodriguez MA, Orlowski RZ, Wang M, Ouzounian ST, Samaniego F, Fayad L. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013 Dec;163(5):611-20. Epub 2013 Oct 1. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00290498
2. Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article PubMed

R-MegaCHOP-14

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chiappella et al. 2017 (DLCL04)	2006-2010	Phase 3 (E-esc)	1. R-CHOP-14	Not reported
			2. R-CHOP-14, then R-MAD, then BEAM, then auto HSCT 3. R-MegaCHOP-14, then R-MAD, then BEAM, then auto HSCT	Did not meet primary endpoint of FFS24

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 1200 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 70 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

14-day cycle for 6 cycles

References

1. Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. Epub 2017 Jun 28. link to original article contains dosing details in abstract PubMed NCT00499018

R-miniCHOP (Rituximab and hyaluronidase)

R-miniCHOP: Rituximab and hyaluronidaase, reduced-dose (mini) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Oberic et al. 2021 (SENIOR)	2014-2017	Phase 3 (C)	R2-miniCHOP	Did not meet primary endpoint of OS

Note: this regimen was intended for patients 80 years or older.

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
• Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
  • Cycles 2 to 6: 1400 mg SC once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV once on day 1
• Vincristine (Oncovin) 1 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

21-day cycle for 6 cycles

References

1. SENIOR: Oberic L, Peyrade F, Puyade M, Bonnet C, Dartigues-Cuillères P, Fabiani B, Ruminy P, Maisonneuve H, Abraham J, Thieblemont C, Feugier P, Salles G, Bijou F, Pica GM, Damaj G, Haioun C, Casasnovas RO, Farhat H, Le Calloch R, Waultier-Rascalou A, Malak S, Paget J, Gat E, Tilly H, Jardin F. Subcutaneous Rituximab-MiniCHOP Compared With Subcutaneous Rituximab-MiniCHOP Plus Lenalidomide in Diffuse Large B-Cell Lymphoma for Patients Age 80 Years or Older. J Clin Oncol. 2021 Apr 10;39(11):1203-1213. Epub 2021 Jan 14. link to original article contains dosing details in manuscript PubMed

R-miniCEOP

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Merli et al. 2012 (ANZINTER3)	2003-2006	Phase 3 (E-de-esc)	R-CHOP	Did not meet primary endpoint of EFS

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Vinblastine (Velban) 5 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 50 mg/m² IV or PO once per day on days 1 to 5

Supportive therapy

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

21-day cycle for 6 cycles

Subsequent treatment

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

References

1. ANZINTER3: Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012 Apr;53(4):581-8. Epub 2011 Nov 15. link to original article contains dosing details in manuscript PubMed NCT01148446

Untreated, non-randomized or retrospective data

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen variant #1, 90 mg/m²

Study	Years of enrollment	Evidence
Park et al. 2016 (LCCC 1011)	2011-2013	Phase 2

Note: this dosing was intended for patients with ECOG PS = 3 at baseline.

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2, given first on day 1
  • Dose increased to 120 mg/m² if ECOG PS improved to less than or equal to 2 after 3 cycles

Targeted therapy

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

21-day cycle for up to 8 cycles

Regimen variant #2, 120 mg/m²

Study	Years of enrollment	Evidence
Park et al. 2016 (LCCC 1011)	2011-2013	Phase 2

Chemotherapy

• Bendamustine 120 mg/m² IV once per day on days 1 & 2, given first on day 1

Targeted therapy

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

21-day cycle for up to 8 cycles

References

1. LCCC 1011: Park SI, Grover NS, Olajide O, Asch AS, Wall JG, Richards KL, Sobol AL, Deal AM, Ivanova A, Foster MC, Muss HB, Shea TC. A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Br J Haematol. 2016 Oct;175(2):281-289. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01234467

Helicobacter pylori eradication therapy

Regimen variant #1, before 1996

Study	Evidence
Kuo et al. 2012	Retrospective

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

Antibiotic therapy

• Amoxicillin 500 mg PO every 6 hours
• Metronidazole (Flagyl) 250 mg PO every 6 hours
• One of the following:
  • Bismuth subcitrate 120 mg PO every 6 hours
  • Omeprazole (Prilosec) 20 mg PO twice per day

28-day course

Regimen variant #2, after 1996

Study	Evidence
Kuo et al. 2012	Retrospective

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

Antibiotic therapy

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

14-day course

References

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

O-miniCHOP

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

Regimen

Study	Years of enrollment	Evidence
Peyrade et al. 2017 (LYSA LNH09-7B)	2010-2011	Phase 2

Preceding treatment

• Vincristine & prednisone pre-phase

Targeted therapy

• Ofatumumab (Arzerra) 1000 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV once on day 1
• Vincristine (Oncovin) 1 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Ofatumumab (Arzerra)
• Diphenhydramine (Benadryl) 50 mg (route not specified) once on day 1, prior to Ofatumumab (Arzerra)

21-day cycle for 6 cycles

References

1. LYSA LNH09-7B: Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F; LYSA. 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 dosing details in abstract PubMed NCT01195714

R-BL

R-BL: Rituximab, Bendamustine, Lenalidomide

Regimen

Study	Years of enrollment	Evidence	Efficacy
Hitz et al. 2016 (SAKK 38/08)	NR	Phase 2, <20 pts in subgroup	ORR: 61% (95% CI 45-76%)

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 2

28-day cycle for 6 cycles

References

1. SAKK 38/08: 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 dosing details in abstract PubMed NCT00987493

R-CDOP

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

Regimen variant #1

Study	Years of enrollment	Evidence
Oki et al. 2014 (MDACC 2004-0305)	2005-NR in abstract	Phase 2

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Pegylated liposomal doxorubicin (Doxil) 40 mg/m² (maximum dose of 90 mg) IV over 60 minutes once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 2 until ANC greater than 3000/μl

OR

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2

Dose modifications

• Dose reduction level 1 (see paper for triggers):
  • Pegylated liposomal doxorubicin (Doxil) reduced to 35 mg/m²
  • Cyclophosphamide (Cytoxan) reduced to 600 mg/m²
• Dose reduction level 2 (see paper for triggers):
  • Pegylated liposomal doxorubicin (Doxil) reduced to 30 mg/m²
  • Cyclophosphamide (Cytoxan) reduced to 450 mg/m²

21-day cycle for 6 to 8 cycles

Regimen variant #2

Study	Years of enrollment	Evidence
Zaja et al. 2006	NR in abstract	Phase 2

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.

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Pegylated liposomal doxorubicin (Doxil) 30 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle for 6 cycles

References

1. Zaja F, Tomadini V, Zaccaria A, Lenoci M, Battista M, Molinari AL, Fabbri A, Battista R, Cabras MG, Gallamini A, Fanin R. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2006 Oct;47(10):2174-80. link to original article PubMed
2. MDACC 2004-0305: Oki Y, Ewer MS, Lenihan DJ, Fisch MJ, Hagemeister FB, Fanale M, Romaguera J, Pro B, Fowler N, Younes A, Astrow AB, Huang X, Kwak LW, Samaniego F, McLaughlin P, Neelapu SS, Wang M, Fayad LE, Durand JB, Rodriguez MA. Pegylated liposomal doxorubicin replacing conventional doxorubicin in standard R-CHOP chemotherapy for elderly patients with diffuse large B-cell lymphoma: an open label, single arm, phase II trial. Clin Lymphoma Myeloma Leuk. 2015 Mar;15(3):152-8. Epub 2014 Sep 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00101010

R-CEOP90 (Epirubicin, Prednisolone)

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

Regimen variant #1, 4 cycles

Study	Years of enrollment	Evidence
Cai et al. 2014	NR in abstract	Phase 2

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).

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 2
• Epirubicin (Ellence) 90 mg/m² IV once on day 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 2

Glucocorticoid therapy

• Prednisolone (Millipred) 100 mg/day PO on days 2 to 6

21-day cycle for 4 cycles

Subsequent treatment

• Patients with stage IA or IIA disease with bulky disease and extranodal and residual masses: IFRT, 30 to 45 Gy

Regimen variant #2, 6 cycles

Study	Years of enrollment	Evidence
Cai et al. 2014	NR in abstract	Phase 2

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).

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 2
• Epirubicin (Ellence) 90 mg/m² IV once on day 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 2

Glucocorticoid therapy

• Prednisolone (Millipred) 100 mg/day PO on days 2 to 6

21-day cycle for 6 cycles

References

1. Cai QC, Gao Y, Wang XX, Cai QQ, Lin ZX, Bai B, Guo Y, Huang HQ. Long-term results of the R-CEOP90 in the treatment of young patients with chemotherapy-naïve diffuse large B cell lymphoma: a phase II study. Leuk Lymphoma. 2014 Oct;55(10):2387-8. link to original article contains dosing details in manuscript PubMed

R-CEOP (Etoposide)

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

Regimen

Study	Evidence
Moccia et al. 2009	Retrospective

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

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Etoposide (Vepesid) 50 mg/m² IV once on day 1, then 100 mg/m² PO once per day on days 2 & 3
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
  • Alternate dosing used in the R-CHOP regimens described in Coiffier et al. 2002 & 2010; Feugier et al. 2005; Mounier et al. 2012 - LNH 98-5 is Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

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

References

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

R-GCVP

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

Regimen

Study	Years of enrollment	Evidence
Fields et al. 2013 (UCL/05/154)	2008-2010	Phase 2

Intended for use in patients unlikely to tolerate anthracyclines due to cardiac comorbidity.

Targeted therapy

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

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 750 mg/m² IV over 30 minutes once per day on days 1 & 8
  • Cycle 2: 875 mg/m² IV over 30 minutes once per day on days 1 & 8
  • Cycles 3 to 6: 1000 mg/m² IV over 30 minutes once per day on days 1 & 8
• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• Acetaminophen (Tylenol) 1000 mg (route not specified) once on day 1, prior to Rituximab (Rituxan)
• Chlorpheniramine (Chlor-Trimeton) 10 mg IV once on day 1, prior to Rituximab (Rituxan)
• Pegfilgrastim (Neulasta) 6 mg SC once on day 9

CNS therapy, 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. UCL/05/154: Fields PA, Townsend W, Webb A, Counsell N, Pocock C, Smith P, Jack A, El-Mehidi N, Johnson PW, Radford J, Linch DC, Cunningham D. De novo treatment of diffuse large B-cell lymphoma with rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac comorbidity: a United kingdom national cancer research institute trial. J Clin Oncol. 2014 Feb 1;32(4):282-7. Epub 2013 Nov 12. link to original article contains dosing details in manuscript PubMed NCT00971763

R-MegaCHOP

R-MegaCHOP: Rituximab, Mega, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne

Regimen

Study	Years of enrollment	Evidence
Pardal et al. 2014 (GELTAMO-2006)	2007-2009	Phase 2

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 1500 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 65 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Pegfilgrastim (Neulasta) given after each cycle

21-day cycle for 3 cycles

Subsequent treatment

• Negative PET-CT after 3 cycles: R-MegaCHOP x 3 for a total of 6 cycles
• Positive PET-CT after 3 cycles: R-IFE

References

1. GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains dosing details in manuscript PubMed NCT013611091

R-miniCHOP

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

Regimen

Study	Years of enrollment	Evidence
Peyrade et al. 2011 (LNH03-7B)	2006-2009	Phase 2

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV once on day 1
• Vincristine (Oncovin) 1 mg IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Supportive therapy

• "Prevention of tumour lysis syndrome by alkalinisation or hypouricaemic drugs was done if necessary."
• Serotonin (5-HT3) antagonist given every cycle.
• Prophylactic G-CSF or erythropoietin was left to treating physician's discretion.
  • Patients with severe neutropenia or neutropenic fever received G-CSF (dose not specified) SC once per day on days 6 to 13 of the subsequent cycle until ANC is greater than or equal to 1000/uL.

21-day cycle for 6 cycles

Dose modifications

• No dose adjustments for hematologic toxicity. If needed, the subsequent R-miniCHOP cycle was postponed until ANC was greater than or equal to 1000/uL and platelet count was greater than or equal to 100 x 10⁹/L, with a maximum of 28 days between cycles. Treatment was stopped if patients' counts were not adequate within 28 days.

References

1. LNH03-7B: 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. 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 dosing details in manuscript PubMed NCT01087424
2. SWOG S1918: NCT04799275

Consolidation after upfront therapy

CBV, then auto HSCT

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Stiff et al. 2013 (SWOG S9704)	1999-2007	Phase 3 (E-esc)	R-CHOP x 8	Superior PFS PFS24: 69% vs 55% (HR 0.58, 95% CI 0.40-0.85)

Preceding treatment

• R-CHOP x 6

Autologous HSCT conditioning regimens

References

1. SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article PubMed NCT00004031
   1. Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article PubMed

CBVM, then auto HSCT

Regimen

Study	Years of enrollment	Evidence
Haioun et al. 2009 (LNH 98-3)	1999-2004	Non-randomized portion of phase 3 RCT

Preceding treatment

• ACE versus ACVBP

Chemotherapy

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

Stem cells reinfused afterwards (unclear which day)

Subsequent treatment

• Observation versus rituximab maintenance

References

1. LNH 98-3: Haioun C, Mounier N, Emile JF, Ranta D, Coiffier B, Tilly H, Récher C, Fermé C, Gabarre J, Herbrecht R, Morchhauser F, Gisselbrecht C. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009 Dec;20(12):1985-92. Epub 2009 Jun 30. link to original article contains dosing details in manuscript PubMed

Cytarabine monotherapy

Regimen

Study	Years of enrollment	Evidence
Récher et al. 2011 (LNH03-2B)	2003-2008	Non-randomized portion of phase III RCT
Ketterer et al. 2013 (LNH03-1B)	2003-2008	Non-randomized portion of phase III RCT

Preceding treatment

• REI consolidation x 4

Chemotherapy

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

14-day cycle for 2 cycles

References

1. LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains dosing details in manuscript PubMed NCT00140595
   1. Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
2. LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed NCT00140595

Ibritumomab tiuxetan protocol

Regimen variant #1, no cap

Study	Years of enrollment	Evidence
Witzig et al. 2015 (ECOG E3402)	2004-2008	Phase 2

Preceding treatment

• R-CHOP x 4 to 6

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days 1 & 8

Radioconjugate therapy

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg IV once on day 8

8-day course

Subsequent treatment

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

Regimen variant #2, capped dose

Study	Years of enrollment	Evidence
Persky et al. 2014 (SWOG S0313)	2004-2008	Phase 2

Preceding treatment

• CHOP x 3, then IFRT

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days 1 & 8 +/- 1 day, given first on day 7, 8, or 9

Radioconjugate therapy

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8 +/- 1 day, given second, within 4 hours of rituximab

References

1. SWOG S0313: Persky DO, Miller TP, Unger JM, Spier CM, Puvvada S, Stea BD, Press OW, Constine LS, Barton KP, Friedberg JW, LeBlanc M, Fisher RI. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. 2015 Jan 8;125(2):236-41. Epub 2014 Nov 13. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070018
2. ECOG E3402: Witzig TE, Hong F, Micallef IN, Gascoyne RD, Dogan A, Wagner H Jr, Kahl BS, Advani RH, Horning SJ. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015 Sep;170(5):679-86. Epub 2015 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00088881

Methotrexate monotherapy

Regimen

Study	Years of enrollment	Evidence
Récher et al. 2011 (LNH03-2B)	2003-2008	Non-randomized portion of phase III RCT
Ketterer et al. 2013 (LNH03-1B)	2003-2008	Non-randomized portion of phase III RCT

Preceding treatment

• R-ACVBP induction x 4

Chemotherapy

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

Supportive therapy

• Calcium folinate - Folinic acid (Leucovorin) rescue

14-day cycle for 2 cycles

Subsequent treatment

• REI consolidation, in 2 weeks

References

1. LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains dosing details in manuscript PubMed NCT00140595
   1. Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
2. LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed NCT00140595

Radiation therapy

Regimen variant #1, testicular irradiation

Study	Years of enrollment	Evidence
Vitolo et al. 2011 (IELSG-10)	2001-2006	Phase 2

Preceding treatment

• R-CHOP x 6 to 8 cycles

Radiotherapy

• External beam radiotherapy 25 to 30 Gy to the contralateral testis. For patients with stage II disease, involved-field radiation therapy was added; see paper for details.

Regimen variant #2, IFRT x 30 Gy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Horning et al. 2004 (ECOG E1484)	1984-1992	Phase 3 (E-esc)	Observation	Seems to have superior DFS

Preceding treatment

• ECOG E1484: CHOP x 8, with CR

Radiotherapy

• IFRT 30 Gy

Regimen variant #3, 36 Gy

Study	Years of enrollment	Evidence
Pfreundschuh et al. 2004 (NHL-B2)	1993-2000	Non-randomized portion of RCT
Pfreundschuh et al. 2008 (RICOVER-60)	2000-2005	Non-randomized portion of phase III RCT
Schmitz et al. 2012 (DSHNHL 2002-1)	2003-2009	Non-randomized portion of phase III RCT
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14)	2007-2009	Phase 2

Preceding treatment

• NHL-B2: CHOEP-14 x 6 versus CHOEP-21 x 6 versus CHOP-14 x 6 versus CHOP-21 x 6
• RICOVER-60: CHOP-14 x 6 versus CHOP-14 x 8 versus R-CHOP-14 x 6 versus R-CHOP-14 x 8
• DSHNHL 2002-1: R-CHOEP-14 x 8 versus R-MegaCHOEP
• SMARTE-R-CHOP-14: R-CHOP-14 x 6

Radiotherapy

• External beam radiotherapy 36 Gy in daily fractions

Regimen variant #4, IFRT x 40 Gy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Horning et al. 2004 (ECOG E1484)	1984-1992	Non-randomized portion of phase III RCT
Bonnet et al. 2007	1993-2002	Phase 3 (C)	Observation	Did not meet primary endpoint of EFS
Persky et al. 2014 (SWOG S0313)	2004-2008	Phase 2
Lamy et al. 2017 (LYSA/GOELAMS 02-03)	2005-2014	Phase 3 (C)	Observation	Non-inferior EFS

Preceding treatment

• ECOG E1484: CHOP x 8, with PR
• SWOG S0313: CHOP x 3, with CR
• Bonnet et al. 2007: CHOP x 4
• LYSA/GOELAMS 02-03: R-CHOP-14 x 4 to 6

Radiotherapy

• External beam radiotherapy 40 Gy in daily fractions of 1.8 to 2 Gy

Subsequent treatment

• SWOG S0313: Ibritumomab tiuxetan consolidation

Regimen variant #5, IFRT x 40 to 55 Gy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Miller et al. 1998 (SWOG S8736)	1988-1995	Phase 3 (E-switch-ooc)	See link	See link
Persky et al. 2008 (SWOG S0014)	2000-2002	Phase 2
Pfreundschuh et al. 2006 (NCIC-CTG LY.9)	2000-2003	Non-randomized portion of phase 3 RCT
Persky et al. 2014 (SWOG S0313)	2004-2008	Phase 2

Note: these studies did not specify an exact dose; see papers for details.

Preceding treatment

• SWOG S8736 and SWOG S0014: CHOP x 3
• NCIC-CTG LY.9: CHOP-like therapy x 6 versus R-CHOP-like therapy x 6
• SWOG S0313: CHOP x 3, with PR

Radiotherapy

• External beam radiotherapy 46 to 50 Gy in daily fractions of 1.8 to 2 Gy

Subsequent treatment

• SWOG S0313: Ibritumumoab tiuxetan consolidation

References

1. SWOG S8736: Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. link to original article contains dosing details in manuscript PubMed NCT00005089
   1. Update: Stephens DM, Li H, LeBlanc ML, Puvvada SD, Persky D, Friedberg JW, Smith SM. Continued risk of relapse independent of treatment modality in limited-stage diffuse large B-cell lymphoma: Final and long-term analysis of Southwest Oncology Group study S8736. J Clin Oncol. 2016 Sep 1;34(25):2997-3004. Epub 2016 Jul 5. link to original article link to PMC article PubMed
2. NHL-B2: Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article contains dosing details in manuscript PubMed
3. ECOG E1484: Horning SJ, Weller E, Kim K, Earle JD, O'Connell MJ, Habermann TM, Glick JH. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004 Aug 1;22(15):3032-8. Epub 2004 Jun 21. link to original article PubMed
4. LNH 93-01: Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, Morel P, Ferme C, Bosly A, Lederlin P, Laurent G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005 Mar 24;352(12):1197-205. link to original article PubMed
5. NCIC-CTG LY.9: Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article PubMed NCT00064116
   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 PubMed
6. Bonnet C, Fillet G, Mounier N, Ganem G, Molina TJ, Thiéblemont C, Fermé C, Quesnel B, Martin C, Gisselbrecht C, Tilly H, Reyes F; Groupe d'Etude des Lymphomes de l'Adulte. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2007 Mar 1;25(7):787-92. Epub 2007 Jan 16. link to original article contains dosing details in manuscript PubMed
7. RICOVER-60: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group. 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 dosing details in manuscript PubMed NCT00052936
8. SWOG S0014: Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, Rimsza LM, Fisher RI, Miller TP; SWOG. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008 May 10;26(14):2258-63. Epub 2008 Apr 14. link to original article does not contain dosing details PubMed
9. IELSG-10: Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Lopez-Guillermo A, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011 Jul 10;29(20):2766-72. Epub 2011 Jun 6. link to original article contains dosing details in manuscript PubMed NCT00210379
10. DSHNHL 2002-1: Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; German High-Grade Lymphoma Study Group. 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 NCT00129090
11. SWOG S0313: Persky DO, Miller TP, Unger JM, Spier CM, Puvvada S, Stea BD, Press OW, Constine LS, Barton KP, Friedberg JW, LeBlanc M, Fisher RI. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. 2015 Jan 8;125(2):236-41. Epub 2014 Nov 13. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070018
12. SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N; German High-Grade Non-Hodgkin Lymphoma Study Group. 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 dosing details in manuscript PubMed NCT00052936
13. LYSA/GOELAMS 02-03: Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, Gressin R, Cornillon J, Banos A, Le Du K, Benchalal M, Moles MP, Le Gouill S, Fleury J, Godmer P, Maisonneuve H, Deconinck E, Houot R, Laribi K, Marolleau JP, Tournilhac O, Branger B, Devillers A, Vuillez JP, Fest T, Colombat P, Costes V, Szablewski V, Béné MC, Delwail V; LYSA. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018 Jan 11;131(2):174-181. Epub 2017 Oct 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00841945

R-IFE

R-IFE: Rituximab, IFosfamide, Etoposide
REI: Rituximab, Etoposide, Ifosfamide

Regimen

Study	Years of enrollment	Evidence
Récher et al. 2011 (LNH03-2B)	2003-2008	Non-randomized portion of phase III RCT
Ketterer et al. 2013 (LNH03-1B)	2003-2008	Non-randomized portion of phase III RCT

Preceding treatment

• Methotrexate consolidation x 2

Targeted therapy

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

Chemotherapy

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

14-day cycle for 4 cycles

Subsequent treatment

• Cytarabine consolidation, in 2 weeks

References

1. LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains dosing details in manuscript PubMed NCT00140595
   1. Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
2. LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed NCT00140595

TBI, then auto HSCT

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Stiff et al. 2013 (SWOG S9704)	1999-2007	Phase 3 (E-esc)	R-CHOP x 8	Superior PFS PFS24: 69% vs 55% (HR 0.58, 95% CI 0.40-0.85)

Preceding treatment

• R-CHOP x 6

Autologous HSCT conditioning regimens Stem cells reinfused on day 0

References

1. SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article PubMed NCT00004031
   1. Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article PubMed

Z-BEAM, then auto HSCT

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

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL)	NR	Randomized Phase 2 (E-esc)	BEAM	Seems to have superior OS
Briones et al. 2013 (GELTAMO Z-BEAM LDCGB)	2008-2010	Phase 2

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once on day -14, given first

Radioconjugate therapy

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2
• Cytarabine (Ara-C) 200 mg/m² IV every 12 hours on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 (Shimoni et al. 2012) or day +7 (GELTAMO Z-BEAM LDCGB) until engraftment
• Valacyclovir (Valtrex) (dose not specified) for one month (Shimoni et al. 2012)
• Acyclovir (Zovirax) (dose not specified) for one month (Briones et al. 2013)
• Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months (3 months in GELTAMO Z-BEAM LDCGB)

One course

Regimen variant #2

Study	Years of enrollment	Evidence
Fruchart et al. 2014 (ZBEAM2)	2007-2008	Phase 2

Preceding treatment

• R-ACVBP or R-CHOP

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days -21 & -14, given first on day -14

Radioconjugate therapy

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
  • Platelet count 150 x 10⁹/L or more: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
  • Platelet count 100 up to 150 x 10⁹/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -7
• Etoposide (Vepesid) 100 mg/m² IV once per day on days -6 to -3
• Cytarabine (Ara-C) 200 mg/m² IV every 12 hours on days -6 to -3
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Supportive therapy

• Autologous stem cells re-infused on day 0
• "According to standard use"

One course

References

1. Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol. 2007 Apr;35(4):534-40. link to original article PubMed
2. SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article contains dosing details in manuscript PubMed NCT00491491
3. GELTAMO Z-BEAM LDCGB: Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2014 Mar;99(3):505-10. Epub 2013 Oct 25. link to original article contains dosing details in manuscript link to PMC article PubMed EudraCT 2007-003198-22
4. ZBEAM2: Fruchart C, Tilly H, Morschhauser F, Ghesquières H, Bouteloup M, Fermé C, Van Den Neste E, Bordessoule D, Bouabdallah R, Delmer A, Casasnovas RO, Ysebaert L, Ciappuccini R, Briere J, Gisselbrecht C. Upfront consolidation combining yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2014 Dec;20(12):1905-11. Epub 2014 Jul 26. link to original article contains dosing details in manuscript PubMed NCT00689169

Maintenance after upfront therapy

Lenalidomide monotherapy

Regimen variant #1, 1 year

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Reddy et al. 2016 (VICC HEM 0835)	2008-2013	Randomized Phase 2 (E-de-esc)	Lenalidomide & Rituximab	Did not meet primary endpoint of RFS12

Preceding treatment

• R-CHOP with or without radiation

Targeted therapy

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

28-day cycle for 12 cycles

Regimen variant #2, 2 years

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thieblemont et al. 2017 (REMARC)	2009-2014	Phase 3 (E-esc)	Placebo	Superior PFS Median PFS: NYR vs 58.9 mo (HR 0.71, 95% CI 0.54-0.93)

Preceding treatment

• R-CHOP-21 or R-CHOP14

Targeted therapy

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

28-day cycle for up to 26 cycles (2 years)

References

1. VICC HEM 0835: Reddy NM, Greer JP, Morgan DS, Chen H, Park SI, Richards KL. A phase II randomized study of lenalidomide or lenalidomide and rituximab as maintenance therapy following standard chemotherapy for patients with high/high-intermediate risk diffuse large B-cell lymphoma. Leukemia. 2017 Jan;31(1):241-244. Epub 2016 Sep 22. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00765245
2. REMARC: Thieblemont C, Tilly H, Gomes da Silva M, Casasnovas RO, Fruchart C, Morschhauser F, Haioun C, Lazarovici J, Grosicka A, Perrot A, Trotman J, Sebban C, Caballero D, Greil R, van Eygen K, Cohen AM, Gonzalez H, Bouabdallah R, Oberic L, Corront B, Choufi B, Lopez-Guillermo A, Catalano J, Van Hoof A, Briere J, Cabeçadas J, Salles G, Gaulard P, Bosly A, Coiffier B. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017 Aug 1;35(22):2473-2481. Epub 2017 Apr 20. link to original article contains dosing details in manuscript PubMed NCT01122472

Rituximab monotherapy

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jaeger et al. 2015 (NHL13)	2004-2010	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of EFS

Patients required to be in CR or CRu prior to enrollment. The protocol was amended after the first 69 patients enrolled to increase length of treatment from 1 to 2 years.

Preceding treatment

• R-CHOP-like chemotherapy x 4 to 8 (8 doses of rituximab)

Targeted therapy

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

2-month cycle for 6 to 12 cycles (1 to 2 years)

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Witzens-Harig et al. 2015 (HD2002)	2002-2011	Phase 3 (E-esc)	Observation	Superior OS in males

Preceding treatment

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

Targeted therapy

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

3-month cycle for 8 cycles (2 years)

Regimen variant #3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Haioun et al. 2009 (LNH 98-3)	1999-2004	Phase 3 (E-esc)	Observation	Might have superior EFS

Preceding treatment

• CBVM, then auto HSCT

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

4-week course

Regimen variant #4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Habermann et al. 2006 (ECOG E4494)	1998-2001	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of FFS

Note: in ECOG E4494, rituximab maintenance had superior FFS in the group receiving CHOP upfront, which is no longer standard of care.

Preceding treatment

• R-CHOP versus CHOP

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

6-month cycle for 4 cycles (2 years)

References

1. ECOG E4494: 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 dosing details in manuscript PubMed NCT00003150
2. LNH 98-3: Haioun C, Mounier N, Emile JF, Ranta D, Coiffier B, Tilly H, Récher C, Fermé C, Gabarre J, Herbrecht R, Morchhauser F, Gisselbrecht C. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009 Dec;20(12):1985-92. Epub 2009 Jun 30. link to original article contains dosing details in manuscript PubMed
3. NHL13: Jaeger U, Trneny M, Melzer H, Praxmarer M, Nawarawong W, Ben Yehuda D, Goldstein D, Mihaljevic B, Ilhan O, Ballova V, Hedenus M, Hsiao LT, Au WY, Burgstaller S, Weidinger G, Keil F, Dittrich C, Skrabs C, Klingler A, Chott A, Fridrik MA, Greil R. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015 Jul;100(7):955-63. Epub 2015 Apr 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00400478
4. HD2002: Witzens-Harig M, Benner A, McClanahan F, Klemmer J, Brandt J, Brants E, Rieger M, Meissner J, Hensel M, Neben K, Dreger P, Lengfelder E, Schmidt-Wolf I, Krämer A, Ho AD. Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma: results of the HD2002 prospective multicentre randomized phase III trial. Br J Haematol. 2015 Dec;171(5):710-9. Epub 2015 Oct 9. link to original article contains dosing details in manuscript PubMed NCT01933711

Relapsed or refractory, salvage therapy

Axicabtagene ciloleucel monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Locke et al. 2021 (ZUMA-7)	2018-2019	Phase 3 (E-RT-switch-ooc)	1. R-ICE 2. R-ESHAP 3. R-DHAP 4. R-GDP	Superior EFS Median EFS: 8.3 vs 2 mo (HR 0.40, 95% CI 0.31-0.51)

Prior treatment criteria

• Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen

Chemotherapy, lymphodepletion

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days -5 to -3 prior to Axicabtagene ciloleucel infusion
• Fludarabine (Fludara) 30 mg/m² IV once per day on days -5 to -3 prior to Axicabtagene ciloleucel infusion

Immunotherapy

• Axicabtagene ciloleucel (Yescarta) target dose of 2 × 10⁶ CAR T cells/kg IV once on day 0

One course

References

1. ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article contains dosing details in manuscript PubMed NCT03391466

Lisocabtagene maraleucel monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kamdar et al. 2022 (TRANSFORM)	2018-2020	Phase 3 (E-RT-switch-ooc)	1. R-ICE 2. R-DHAP 3. R-GDP	Superior EFS Median EFS: 10.1 vs 2.3 mo (HR 0.35, 95% CI 0.23-0.53)

Immunotherapy

• Lisocabtagene maraleucel (Breyanzi)

References

1. TRANSFORM: Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. link to original article PubMed NCT03575351

O-DHAP

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Matasar et al. 2013 (GSK 110927)	2009-2011	Phase 2
van Imhoff et al. 2016 (ORCHARRD)	2010-2013	Phase 3 (E-switch-ic)	R-DHAP	Did not meet primary endpoint of PFS

Targeted therapy

• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 1000 mg IV once per day on days 1 & 8
  • Cycles 2 & 3: 1000 mg IV once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4

Chemotherapy

• Cytarabine (Ara-C) 2000 mg/m² IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1

Supportive therapy

• GSK 110927 recommended: Filgrastim (Neupogen) or Pegfilgrastim (Neulasta)

21-day cycle for 3 cycles

Subsequent treatment

• GSK 110927, responders: Stem-cell mobilization and autologous hematopoietic stem cell transplant (regimen not specified)
• ORCHARRD, responders: BEAM with autologous hematopoietic stem cell transplant except those in Japan who received LEED with autologous hematopoietic stem cell transplant

References

1. GSK 110927: Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. Epub 2013 May 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00823719
2. ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: The ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement contains dosing details in supplement PubMed NCT01014208

O-ICE

O-ICE: Ofatumumab, Ifosfamide, Carboplatin, Etoposide

Regimen

Study	Years of enrollment	Evidence
Matasar et al. 2013 (GSK 110927)	2009-2011	Phase 2

Note: Subsequent consolidation therapy was not specified.

Targeted therapy

• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 1000 mg IV once per day on days 1 & 8
  • Cycles 2 & 3: 1000 mg IV once on day 1

Chemotherapy

• Ifosfamide (Ifex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 2, mixed with mesna
• Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on either day 1 or 2
  • Carboplatin AUC calculated based on a 12-hour creatinine clearance
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

Supportive therapy

• Mesna (Mesnex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 2, mixed with Ifosfamide (Ifex)
• Recommended: Filgrastim (Neupogen) or Pegfilgrastim (Neulasta)

21-day cycle for 3 cycles

References

1. GSK 110927: Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. Epub 2013 May 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00823719

R-DexaBEAM

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

Regimen

Study	Years of enrollment	Evidence
Kirschey et al. 2014 (Mz-135)	2002-2006	Phase 2

Note: the dosing in the manuscript is different than below. The below are the correct doses as verified by the authors.

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 8

Glucocorticoid therapy

• Dexamethasone (Decadron) 8 mg PO three times per day on days 1 to 10

Chemotherapy

• Carmustine (BCNU) 60 mg/m² IV once on day 3
• Etoposide (Vepesid) 75 mg/m² IV once per day on days 4 to 7
• Cytarabine (Ara-C) 100 mg/m² IV twice per day on days 4 to 7
• Melphalan (Alkeran) 20 mg/m² IV once on day 2

3- to 4-week cycle for 2 cycles

Subsequent treatment

• R-BEAM with autologous hematopoietic stem cell transplant or R-TBI/Cy with autologous hematopoietic stem cell transplant

References

1. Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article contains dosing details in manuscript PubMed NCT02099292

R-DHAOx

R-DHAOx: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin
ROAD: Rituximab, Oxaliplatin, Ara-C (Cytarabine), Dexamethasone

Regimen

Study	Years of enrollment	Evidence	Efficacy
Witzig et al. 2017 (MCCRC MC0485)	Phase 2	2006-2008	ORR: 71% (95% CI, 56–84)

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5

Chemotherapy

• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours once per day on days 2 & 3, second dose to be given no sooner than 12 hours and no later than 24 hours after end of first dose
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 2

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 4

21-day cycles

Subsequent treatment

• Most responders proceeded to high-dose chemotherapy with autologous hematopoietic stem cell transplant after 2 cycles, although this was not mandated in the protocol

References

1. MCCRC MC0485: Witzig TE, Johnston PB, LaPlant BR, Kurtin PJ, Pederson LD, Moore DF Jr, Nabbout NH, Nikcevich DA, Rowland KM, Grothey A. Long-term follow-up of chemoimmunotherapy with rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma: Results of a study of the Mayo Clinic Cancer Center Research Consortium (MCCRC) MC0485 now known as academic and community cancer research united (ACCRU). Am J Hematol. 2017 Oct;92(10):1004-1010. Epub 2017 Aug 17. link to original article contains dosing details in manuscript PubMed NCT00166439

R-DHAP

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

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gisselbrecht et al. 2010 (CORAL)	2003-2007	Phase 3 (E-switch-ic)	R-ICE	Did not meet primary endpoint of mobilization-adjusted response rate after 3 cycles
van Imhoff et al. 2016 (ORCHARRD)	2010-2013	Phase 3 (C)	O-DHAP	Did not meet primary endpoint of PFS

Note: CORAL makes reference to Velasquez et al. 1988 to describe this regimen, although this reference is for DHAP, not R-DHAP. The paper also contains the following regimen information:

Targeted therapy

• Rituximab (Rituxan) as follows, given first:
  • Cycle 1: 375 mg/m² IV once per day on days -1 & 1 (CORAL) or days 1 & 8 (ORCHARRD)
  • Cycle 2: 375 mg/m² IV once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Chemotherapy

• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1

Supportive therapy

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

21-day cycle for 3 cycles

Subsequent treatment

• CORAL, responders: BEAM with autologous hematopoietic stem cell transplant
• ORCHARRD, responders: BEAM with autologous hematopoietic stem cell transplant except those in Japan who received LEED with autologous hematopoietic stem cell transplant

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Crump et al. 2014 (NCIC-CTG LY.12)	2003-2011	Phase 3 (C)	R-GDP	Non-inferior RR after 2 cycles
Locke et al. 2021 (ZUMA-7)	2018-2019	Phase 3 (C)	Axicabtagene ciloleucel	Inferior EFS
Bishop et al. 2021 (BELINDA)	2019-2021	Phase 3 (C)	Tisagenlecleucel	Did not meet primary endpoint of EFS Median EFS: 3 vs 3 mo (HR 0.93, 95% CI 0.71-1.22)

Prior treatment criteria

• NCIC-CTG LY.12: Previous treatment with one anthracycline-containing chemotherapy regimen
• ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen

Targeted therapy

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

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Chemotherapy

• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1

21-day cycle for up to 3 cycles

Subsequent treatment

• Responders: Stem-cell mobilization and high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)

Regimen variant #3

Study	Years of enrollment	Evidence
Mey et al. 2006	NR in abstract	Phase 2

The doses here were used after a mid-protocol amendment pertaining to the first cycle, and are intended for patients younger than 60 years of age.

Targeted therapy

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

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 3 to 5
  • Cycles 2 to 4: 40 mg PO once per day on days 3 to 6

Chemotherapy

• Cytarabine (Ara-C) as follows:
  • Cycle 1: 1000 mg/m² IV over 2 hours every 12 hours on day 4 (total dose per cycle: 2000 mg/m²)
  • Cycles 2 to 4: 2000 mg/m² IV over 2 hours every 12 hours on day 4 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) as follows:
  • Cycle 1: 25 mg/m²/day IV continuous infusion over 72 hours, started on day 3 (total dose: 75 mg/m²)
  • Cycles 2 to 4: 25 mg/m²/day IV continuous infusion over 96 hours, started on day 3 (total dose per cycle: 100 mg/m²)

21-day cycle for up to 4 cycles

Subsequent treatment

• Patients with at least PR were allowed to undergo high-dose chemotherapy with autologous stem-cell transplant (regimen not specified)

Regimen variant #3

Study	Years of enrollment	Evidence
Mey et al. 2006	NR in abstract	Phase 2

The doses here were used after a mid-protocol amendment pertaining to the first cycle, and are intended for patients older than 60 years of age.

Targeted therapy

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

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycle 1: 40 mg PO once per day on days 3 to 5
  • Cycles 2 to 4: 40 mg PO once per day on days 3 to 6

Chemotherapy

• Cytarabine (Ara-C) as follows:
  • Cycle 1: 500 mg/m² IV over 2 hours every 12 hours on day 4 (total dose per cycle: 1000 mg/m²)
  • Cycles 2 to 4: 1000 mg/m² IV over 2 hours every 12 hours on day 4 (total dose per cycle: 2000 mg/m²)
• Cisplatin (Platinol) as follows:
  • Cycle 1: 25 mg/m²/day IV continuous infusion over 72 hours, started on day 3 (total dose: 75 mg/m²)
  • Cycles 2 to 4: 25 mg/m²/day IV continuous infusion over 96 hours, started on day 3 (total dose per cycle: 100 mg/m²)

21-day cycle for up to 4 cycles

Subsequent treatment

• Patients with at least PR were allowed to undergo high-dose chemotherapy with autologous stem-cell transplant (regimen not specified)

References

1. Mey UJ, Orlopp KS, Flieger D, Strehl JW, Ho AD, Hensel M, Bopp C, Gorschlüter M, Wilhelm M, Birkmann J, Kaiser U, Neubauer A, Florschütz A, Rabe C, Hahn C, Glasmacher AG, Schmidt-Wolf IG. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest. 2006 Oct;24(6):593-600. link to original article contains dosing details in manuscript PubMed
2. CORAL: Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00137995
3. NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains dosing details in manuscript PubMed NCT00078949
4. ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement contains dosing details in supplement PubMed NCT01014208
5. ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article contains dosing details in supplement PubMed NCT03391466
6. BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article contains dosing details in supplement PubMed NCT03570892

R-DHAP/R-VIM

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Vellenga et al. 2008 (HOVON-44)	2000-2005	Phase 3 (E-esc)	DHAP/VIM	Superior PFS

Note: per the paper, "in case patients were non-responsive to R-DHAP but responsive to R-VIM, it was allowed to repeat the R-VIM regimen as the third cycle of reinduction chemotherapy." No statement is made as to whether Mesna is used in the VIM protocol.

Targeted therapy, R-DHAP portion

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 3: 375 mg/m² IV once on day 5

Glucocorticoid therapy, R-DHAP portion

• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 3: 40 mg IV or PO once per day on days 1 to 4

Chemotherapy, R-DHAP portion

• Cytarabine (Ara-C) as follows:
  • Cycles 1 & 3: 2000 mg/m² IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) as follows:
  • Cycles 1 & 3: 100 mg/m² IV continuous infusion over 24 hours, started on day 1

Targeted therapy, R-VIM portion

• Rituximab (Rituxan) as follows:
  • Cycle 2: 375 mg/m² IV once on day 6

Chemotherapy, R-VIM portion

• Etoposide (Vepesid) as follows:
  • Cycle 2: 90 mg/m² IV once per day on days 1, 3, 5
• Ifosfamide (Ifex) as follows:
  • Cycle 2: 1200 mg/m² IV once per day on days 1 to 5
• Methotrexate (MTX) as follows:
  • Cycle 2: 30 mg/m² IV once per day on days 1 & 5

28-day cycle for 3 cycles

Subsequent treatment

• Responders: Stem-cell mobilization, then BEAM with autologous hematopoietic stem cell transplant

References

1. HOVON-44: Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15;111(2):537-43. link to original article contains dosing details in manuscript PubMed NCT00012051

R-EPOCH

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

Regimen

Study	Years of enrollment	Evidence
Jermann et al. 2004	1998-2001	Phase 2

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

Targeted therapy

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

Chemotherapy

• Etoposide (Vepesid) 65 mg/m²/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 195 mg/m²)
• Vincristine (Oncovin) 0.5 mg/m²/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 1.5 mg/m²)
• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 5
• Doxorubicin (Adriamycin) 15 mg/m²/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 45 mg/m²)

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14

21-day cycle for 4 to 6 cycles

Subsequent treatment

• Patients younger than 60 who achieved at least PR: High-dose chemotherapy with autologous hematopoietic stem-cell transplantation (regimen not specified)

References

1. Jermann M, Jost LM, Taverna Ch, Jacky E, Honegger HP, Betticher DC, Egli F, Kroner T, Stahel RA. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004 Mar;15(3):511-6. link to original article contains dosing details in manuscript PubMed

R-ESHAP

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2008	2000-2007	Retrospective
Avilés et al. 2010	NR	Phase 3 (E-esc)	ESHAP	Did not meet efficacy endpoints
Locke et al. 2021 (ZUMA-7)	2018-2019	Phase 3 (C)	Axicabtagene ciloleucel	Inferior EFS

Regimen details are based on the ZUMA-7 protocol, which makes reference to Martin et al. 2008.

Prior treatment criteria

• ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen

Targeted therapy

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

Chemotherapy

• Etoposide (Vepesid) 40 mg/m² IV once per day on days 1 to 4
• Cytarabine (Ara-C) 2000 mg/m² IV once on day 5
• Cisplatin (Platinol) 25 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 100 mg/m²)

Glucocorticoid therapy

• Methylprednisolone (Solumedrol) 500 mg IV once per day on days 1 to 4 or 1 to 5

References

1. Retrospective: Martín A, Conde E, Arnan M, Canales MA, Deben G, Sancho JM, Andreu R, Salar A, García-Sanchez P, Vázquez L, Nistal S, Requena MJ, Donato EM, González JA, León A, Ruiz C, Grande C, González-Barca E, Caballero MD; Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea. 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 dosing details in manuscript PubMed
2. Avilés A, Neri N, Huerta-Guzmán J, de Jesús Nambo M. ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2010 Apr;10(2):125-8. link to original article PubMed
3. ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article contains dosing details in supplement PubMed NCT03391466

R-GDP

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

Regimen variant #1, 1 day of cisplatin/cycle

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Crump et al. 2014 (NCIC-CTG LY.12)	2003-2011	Phase 3 (E-switch-ic)	R-DHAP	Non-inferior RR after 2 cycles
Locke et al. 2021 (ZUMA-7)	2018-2019	Phase 3 (C)	Axicabtagene ciloleucel	Inferior EFS
Bishop et al. 2021 (BELINDA)	2019-2021	Phase 3 (C)	Tisagenlecleucel	Did not meet primary endpoint of EFS Median EFS: 3 vs 3 mo (HR 0.93, 95% CI 0.71-1.22)

Prior treatment criteria

• NCIC-CTG LY.12: Previous treatment with one anthracycline-containing chemotherapy regimen
• ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen

Targeted therapy

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Cisplatin (Platinol) 75 mg/m² IV once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

21-day cycle for up to 3 cycles

Subsequent treatment

• Responders: Stem-cell mobilization and high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)

Regimen variant #2, 3 days of cisplatin/cycle

Study	Years of enrollment	Evidence
Hou et al. 2012	2005-2010	Non-randomized

Targeted therapy

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1 to 3

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 4

21-day cycle for up to 6 cycles

References

1. Hou Y, Wang HQ, Ba Y. Rituximab, gemcitabine, cisplatin, and dexamethasone in patients with refractory or relapsed aggressive B-cell lymphoma. Med Oncol. 2012 Dec;29(4):2409-16. Epub 2012 Apr 3. link to original article PubMed
2. NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains dosing details in manuscript PubMed NCT00078949
3. ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article contains dosing details in supplement PubMed NCT03391466
4. BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article contains dosing details in supplement PubMed NCT03570892

R-GemOx

R-GemOx: Rituximab, Gemcitabine, Oxaliplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bishop et al. 2021 (BELINDA)	2019-2021	Phase 3 (C)	Tisagenlecleucel	Did not meet primary endpoint of EFS Median EFS: 3 vs 3 mo (HR 0.93, 95% CI 0.71-1.22)

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

Targeted therapy

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once on day 2
• Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 1

15-day cycle for 2 or more cycles

Subsequent treatment

• Responders: Stem-cell mobilization and high-dose chemotherapy with autologous hematopoietic stem cell transplant (BEAM preferred)

References

1. BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article contains dosing details in supplement PubMed NCT03570892

R-ICE

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

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gisselbrecht et al. 2010 (CORAL)	2003-2007	Phase 3 (E-switch-ic)	R-DHAP	Did not meet primary endpoint of mobilization-adjusted response rate after 3 cycles
Fayad et al. 2015 (SG040-0005)	2007-2009	Randomized Phase 2b (C)	R-ICE & Dacetuzumab	Did not meet primary endpoint of CR rate
Locke et al. 2021 (ZUMA-7)	2018-2019	Phase 3 (C)	Axicabtagene ciloleucel	Inferior EFS
Bishop et al. 2021 (BELINDA)	2019-2021	Phase 3 (C)	Tisagenlecleucel	Did not meet primary endpoint of EFS Median EFS: 3 vs 3 mo (HR 0.93, 95% CI 0.71-1.22)

Note: Gisselbrecht et al. 2010 refers to the non-randomized regimen described in variant #3 below, although it has slightly different day numbering. Doses are the same. ZUMA-7 & BELINDA describe just one dose of rituximab per cycle, given on the day prior to chemotherapy.

Prior treatment criteria

• ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen

Targeted therapy

• Rituximab (Rituxan) as follows (given first before other chemotherapy; see note):
  • Cycle 1: 375 mg/m² IV once per day on days -1 & 1
  • Cycles 2 & 3: 375 mg/m² IV once on day 1

Chemotherapy

• Ifosfamide (Ifex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 2
• Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 2
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

Supportive therapy

• Mesna (Mesnex) given with Ifosfamide (Ifex) (dose & schedule not specified)
• " Granulocyte colony-stimulating factor was administered after R-ICE"

21-day cycle for 2 to 3 cycles

Subsequent treatment

• Complete or partial response: BEAM with autologous hematopoietic stem cell transplant

Regimen variant #2

Study	Evidence	Efficacy
Guo et al. 2014	Phase 2	ORR: 78%

Note: original article is in Chinese; this information is from the English abstract.

Targeted therapy

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

Chemotherapy

• Ifosfamide (Ifex) 1600 mg/m² IV once per day on days 2 to 4
• Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 3
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 4

3 cycles; duration of cycles not specified in the abstract

Regimen variant #3

Study	Years of enrollment	Evidence	Efficacy
Zelenetz et al. 2003	1993-2000	Phase 2	ORR: 81%
Kewalramani et al. 2004	NR in abstract	Phase 2	ORR: 78%

Third cycle intended to be followed by peripheral blood hematopoietic stem cell collection. ORR reported in Zelenetz et al. 2003 is for the subset of DLBCL patients who received R-ICE; it is unclear if these patients were exposed to rituximab previously. None of the patients in Kewalaramani et al. 2004 had previously received rituximab.

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days -2 & 1
  • Cycles 2 & 3: 375 mg/m² IV once on day 1

Chemotherapy

• Ifosfamide (Ifex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 4, mixed with mesna
• Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV bolus once on day 4
  • Carboplatin AUC calculated based on a 12-hour creatinine clearance
• Etoposide (Vepesid) 100 mg/m² IV bolus once per day on days 3 to 5

Supportive therapy

• (as described by Kewalramani et al. 2004):
• Mesna (Mesnex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 4, mixed with Ifosfamide (Ifex)
• Acetaminophen (Tylenol) 650 mg PO once as premedication for Rituximab (Rituxan)
• Diphenhydramine (Benadryl) 50 mg IV once as premedication for Rituximab (Rituxan)
• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 14 (10 mcg/kg with cycle 3, given until collection of peripheral blood hematopoietic stem cells)

14-day cycle for 3 cycles

References

1. Zelenetz AD, Hamlin P, Kewalramani T, Yahalom J, Nimer S, Moskowitz CH. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2003;14 Suppl 1:i5-10. link to original article contains dosing details in manuscript 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 dosing details in abstract PubMed
3. CORAL: Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00137995
4. Guo Y, Chen Y, Hong X, Yu L, Ma J, Shi Y, Liu T, Jiang W, Zhu J, Jin J, Zou P, Wu D, Shen Z. [A phase II multicenter study to investigate R-ICE as a salvage therapy for relapsed diffuse large B-cell lymphoma]. Zhonghua Xue Ye Xue Za Zhi. 2014 Apr;35(4):314-7. Chinese. link to original article contains dosing details in abstract PubMed
5. SG040-0005: Fayad L, Ansell SM, Advani R, Coiffier B, Stuart R, Bartlett NL, Forero-Torres A, Kuliczkowski K, Belada D, Ng E, Drachman JG. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leuk Lymphoma. 2015;56(9):2569-78. Epub 2015 Feb 26. link to original article PubMed NCT00529503
6. ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article contains dosing details in supplement PubMed NCT03391466
7. BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article contains dosing details in supplement PubMed NCT03570892

RICER

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

Regimen

Study	Years of enrollment	Evidence
Feldman et al. 2014 (RV-DLBCL-PI-0463)	2010-2012	Phase 2

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 7

Chemotherapy

• Ifosfamide (Ifex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 2, mixed with mesna
• Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 2
• Etoposide (Vepesid) 100 mg/m² IV bolus once per day on days 2 to 4

Supportive therapy

• Mesna (Mesnex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 2, mixed with Ifosfamide (Ifex)
• Aspirin 81 mg PO once per day from day 1 until platelets less than 50 × 10⁹/L
• Low dose LMWH for patients intolerant of Aspirin
• " Granulocyte colony-stimulating factor was administered after R-ICE"

14-day cycle for 2 cycles

Subsequent treatment

• Responders received a 3rd cycle with hematopoietic stem cell collection 10 to 14 days afterwards, then BEAM with autologous hematopoietic stem cell transplant (details not described)

References

1. RV-DLBCL-PI-0463: Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. Epub 2014 Mar 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01241734

R-IFE

R-IFE: Rituximab, IFosfamide, Etoposide

Regimen

Study	Years of enrollment	Evidence
Pardal et al. 2014 (GELTAMO-2006)	2007-2009	Phase 2

These were patients with PET-positive disease at interim assessment.

Preceding treatment

• R-MegaCHOP x 3

Targeted therapy

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

Chemotherapy

• Ifosfamide (Ifex) 3333 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 10,000 mg/m²)
• Etoposide (Vepesid) 150 mg/m² IV over 12 hours once per day on days 1 to 3

Supportive therapy

• Mesna (Mesnex) given after R-IFE; details not supplied in manuscript
• Pegfilgrastim (Neulasta) given after each cycle

2 cycles (duration not specified)

Subsequent treatment

• Responders: BEAM with autologous hematopoietic stem cell transplant

References

1. GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains dosing details in manuscript PubMed NCT013611091

R-NIMP

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

Regimen

Study	Years of enrollment	Evidence	Efficacy
Gyan et al. 2013	2004-2010	Phase 2	68% (95% CI: 53–79)

BSA was capped at 2 for all dose calculations.

Targeted therapy

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

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 15
• Ifosfamide (Ifex) 1000 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m²)
• Mitoxantrone (Novantrone) 10 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 1 mg/kg (route not specified) once per day on days 1 to 5

Supportive therapy

• Mesna (Mesnex) given with Ifosfamide (Ifex) "at the same dose"; schedule not specified in the paper
• Recommended: Pegfilgrastim (Neulasta) 6 mg SC once on day 7
• Recommended: Epoietin alpha support for hemoglobin less than 10 g/dL

28-day cycle for 3 cycles

Subsequent treatment

• Responders were recommended to undergo 3 additional cycles of R-NIMP (if transplant ineligible) or high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)

References

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. 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 dosing details in manuscript PubMed

Consolidation after salvage therapy

BEAC, then auto HSCT

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Philip et al. 1991 (Parma)	1986-1987	Prospective pilot
Philip et al. 1995 (PARMA)	1987-1994	Phase 3 (E-esc)	DHAP x 4	Seems to have superior OS

Preceding treatment

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

References

1. Philip T, Chauvin F, Armitage J, Bron D, Hagenbeek A, Biron P, Spitzer G, Velasquez W, Weisenburger DD, Fernandez-Ranada J, Somers R, Rizzoli V, Harousseau JL, Sotto JJ, Cahn JY, Guilhot F, Biggs J, Sonneveld P, Misset JL, Manna A, Jagannath S, Guglielmi C, Chevreau C, Delmer A, Santini G, Coiffier B. Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation. Blood. 1991 Apr 1;77(7):1587-92. link to original article contains dosing details in manuscript PubMed
2. PARMA: Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, Coiffier B, Biron P, Mandelli F, Chauvin F. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7;333(23):1540-5. link to original article PubMed

BEAM, then allo HSCT

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

Regimen

Study	Years of enrollment	Evidence
Przepiorka et al. 1999	NR	Phase 2

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 200 mg/m² IV twice per day on days -5 to -2
• Cytarabine (Ara-C) 200 mg/m² IV twice per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Tacrolimus (Prograf)
• Methotrexate (MTX)

Supportive therapy

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

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, Ueno NT, Molldrem J, Mehra R, Körbling M, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, Andersson B, Anderlini P, Champlin R. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol. 1999 May;10(5):527-32. link to original article contains dosing details in abstract PubMed

BEAM, then auto HSCT

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

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL)	NR	Randomized Phase 2 (C)	Z-BEAM	Seems to have inferior OS
Pardal et al. 2014 (GELTAMO-2006)	2007-2009	Phase 2
van Imhoff et al. 2016 (ORCHARRD)	2010-2013	Non-randomized portion of phase 3 RCT

Preceding treatment

• GELTAMO-2006: R-MegaCHOP x 3, then R-IFE x 2
• ORCHARRD: O-DHAP x 3 versus R-DHAP x 3

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2
• Cytarabine (Ara-C) 200 mg/m² IV every 12 hours on days -5 to -2 (total dose: 1600 mg/m²)
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0
• Variously described:
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 "until engraftment"
• Valacyclovir (Valtrex) (dose not specified) for one month
• Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months

One course

Stem cells reinfused on day 0

Regimen variant #2

Study	Years of enrollment	Evidence
Vellenga et al. 2008 (HOVON-44)	2000-2005	Non-randomized portion of phase 3 RCT
Gisselbrecht et al. 2010 (CORAL)	2003-2007	Non-randomized portion of phase 3 RCT

Preceding treatment

• HOVON-44: DHAP/VIM versus R-DHAP/R-VIM
• CORAL: R-ICE x 3 versus R-DHAP x 3

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2
• Cytarabine (Ara-C) 200 mg/m² IV once per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

Stem cells reinfused on day 0

Subsequent treatment

• CORAL: Rituximab maintenance versus observation

Regimen variant #3, 300/100q12/200/140

Study	Years of enrollment	Evidence
Philip et al. 1987	1980-1985	Non-randomized

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes every 12 hours on days 2 to 5 (total dose: 800 mg/m²)
• Cytarabine (Ara-C) 200 mg/m² IV once per day on days 2 to 5
• Melphalan (Alkeran) 140 mg/m² IV over 5 minutes once on day 6

Supportive therapy

• Autologous stem cells re-infused on unspecified day

One course

References

1. Philip T, Armitage JO, Spitzer G, Chauvin F, Jagannath S, Cahn JY, Colombat P, Goldstone AH, Gorin NC, Flesh M, Laporte JP, Maraninchi D, Pico J, Bosly A, Anderson C, Schots R, Biron P, Cabanillas F, Dicke K. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 1987 Jun 11;316(24):1493-8. link to original article contains dosing details in manuscript PubMed
2. HOVON-44: Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15;111(2):537-43. link to original article contains dosing details in manuscript PubMed NCT00012051
3. CORAL: Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00137995
4. SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article contains dosing details in manuscript PubMed NCT00491491
5. GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains dosing details in manuscript PubMed NCT013611091
6. ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement contains dosing details in supplement PubMed NCT01014208

BeEAM, then auto HSCT

BeEAM: Bendamustine, Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study	Years of enrollment	Evidence
Visani et al. 2011	2008-2010	Phase 1/2, <20 pts in this subgroup

Chemotherapy

• Bendamustine 200 mg/m² IV once per day on days -7 & -6
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2
• Cytarabine (Ara-C) 400 mg/m² IV once per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. Visani G, Malerba L, Stefani PM, Capria S, Galieni P, Gaudio F, Specchia G, Meloni G, Gherlinzoni F, Giardini C, Falcioni S, Cuberli F, Gobbi M, Sarina B, Santoro A, Ferrara F, Rocchi M, Ocio EM, Caballero MD, Isidori A. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011 Sep 22;118(12):3419-25. Epub 2011 Aug 3. link to original article contains dosing details in manuscript PubMed EudraCT 2008-002736-15

CBV, then auto HSCT

CBV: Cyclophosphamide, BiCNU (Carmustine), VP-16 (Etoposide)

Regimen

Study	Years of enrollment	Evidence
Stiff et al. 1998	NR in abstract	Phase 2

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/kg IV over 2 hours once on day -2
• Carmustine (BCNU) 15 mg/kg (maximum dose of 550 mg/m²) IV over 60 minutes once on day -6
• Etoposide (Vepesid) 60 mg/kg IV over 4 hours once on day -4

Supportive therapy

• Autologous stem cells re-infused on day 0
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4, to continue until ANC greater than 5000/μL once or greater than 1500/μL twice
• Levofloxacin (Levaquin) 500 mg PO once per day, starting on day +2, to continue until ANC at least 500/μL
• Fluconazole (Diflucan) 200 mg PO once per day, starting on day +1, to continue until ANC at least 500/μL
• Acyclovir (Zovirax) 200 mg PO three times per day, starting on day -2, to continue until 1 year after HSCT
• Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day on Saturday and Sunday, to continue until 3 months after HSCT

Additional considerations

If any patient appeared to be experiencing carmustine-induced pneumonitis:

• Prednisone (Sterapred) 0.5 mg/kg PO twice per day x 2 weeks, then tapered over 4 weeks

One course

References

1. Stiff PJ, Dahlberg S, Forman SJ, McCall AR, Horning SJ, Nademanee AP, Blume KG, LeBlanc M, Fisher RI; SWOG. Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial. J Clin Oncol. 1998 Jan;16(1):48-55. link to original article contains dosing details in manuscript PubMed

Cyclophosphamide & TBI, then auto HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence
Phillips et al. 1984	1977-1982	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Radiotherapy

• Total body irradiation (TBI) 1200 cGy in fractions on days –6 to –4 (pulmonary dosage was limited to 800 cGy)

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. Phillips GL, Herzig RH, Lazarus HM, Fay JW, Wolff SN, Mill WB, Lin H, Thomas PR, Glasgow GP, Shina DC, Herzig GP. Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow. N Engl J Med. 1984 Jun 14;310(24):1557-61. link to original article PubMed

FEAM, then auto HSCT

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

Regimen

Study	Years of enrollment	Evidence
Musso et al. 2009	2007-2008	Phase 2

Chemotherapy

• Fotemustine (Muphoran) 150 mg/m² IV once per day on days -7 & -6 (total dose: 300 mg/m²)
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2 (total dose: 800 mg/m²)
• Cytarabine (Ara-C) 400 mg/m² IV once per day on days -5 to -2 (total dose: 1600 mg/m²)
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. Musso M, Scalone R, Marcacci G, Lanza F, Di Renzo N, Cascavilla N, Di Bartolomeo P, Crescimanno A, Perrone T, Pinto A. Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study. Bone Marrow Transplant. 2010 Jul;45(7):1147-53. Epub 2009 Nov 9. link to original article PubMed

FluBuCy, then allo HSCT

FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-2009	Phase 2

Chemotherapy

• Fludarabine (Fludara) 25 mg/m²/day IV on days -8 to -4
• Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -4
• Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose)
  • Option also to use ATG-Fresenius S at a higher dose of 10 mg/kg
• Tacrolimus (Prograf) 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
• Mycophenolate mofetil (CellCept) 1000 mg (route not specified) twice per day from day +1 to +28

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. DSHNHL R3: Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. link to original article link to original protocol (in German) contains dosing details in manuscript PubMed NCT00785330

Fludarabine, Busulfan, ATG, Ibritumomab tiuxetan, then allo HSCT

Regimen

Study	Years of enrollment	Evidence
Bouabdallah et al. 2015 (ZEVALLO)	2008-2010	Phase 2

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -6 to -2
• Busulfan (Myleran) 3.2 mg/kg/day (route not specified) on days -5 & -4

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days -21 & -14

Radioconjugate therapy

• Ibritumomab tiuxetan (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2.5 mg/kg IV once on day -1
• Cyclosporine (dose not specified) until day +90 and tapered off by day +180 based on chimerism and GVHD
• Methotrexate (MTX) by the following donor-based criteria:
  • Unrelated donors with HLA mismatch: 15 mg/m² (route not specified) once on day +1, then 10 mg/m² (route not specified) once per day on days +3 & +6

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. ZEVALLO: Bouabdallah K, Furst S, Asselineau J, Chevalier P, Tournilhac O, Ceballos P, Vigouroux S, Tabrizi R, Doussau A, Bouabdallah R, Mohty M, Le Gouill S, Blaise D, Milpied N. 90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. Ann Oncol. 2015 Jan;26(1):193-8. Epub 2014 Oct 30. link to original article contains dosing details in manuscript PubMed NCT00607854

LEED, then auto HSCT

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

Regimen

Study	Years of enrollment	Evidence
van Imhoff et al. 2016 (ORCHARRD)	2010-2013	Non-randomized portion of phase III RCT

Preceding treatment

• O-DHAP x 3 versus R-DHAP x 3

Autologous HSCT conditioning regimens Stem cells reinfused on day 0

References

1. ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement contains dosing details in supplement PubMed NCT01014208

R-BEAM, then auto HSCT

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

Regimen variant #1, 750/300/800/800/140

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Vose et al. 2013 (BMT CTN 0401)	2006-2009	Phase 3 (C)	B-BEAM	Did not meet primary endpoint of PFS24

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

Targeted therapy

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

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 100 mg/m² IV twice per day on days -5 to -2
• Cytarabine (Ara-C) 100 mg/m² IV twice per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

Regimen variant #2, 750/300/1600/3200/140

Study	Years of enrollment	Evidence
Kirschey et al. 2014 (Mz-135)	2002-2006	Phase 2

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

Preceding treatment

• R-DexaBEAM x 2

Autologous HSCT conditioning regimens

References

1. BMT CTN 0401: Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, Fenske T, Horowitz M, Fisher R, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013 May 1;31(13):1662-8. Epub 2013 Mar 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00329030
2. Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article contains dosing details in manuscript PubMed NCT02099292

R-TBI/Cy, then auto HSCT

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

Regimen

Study	Years of enrollment	Evidence
Kirschey et al. 2014 (Mz-135)	2002-2006	Phase 2

Preceding treatment

• R-DexaBEAM x 2

Autologous HSCT conditioning regimens Stem cells reinfused on day 0

References

1. Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article contains dosing details in manuscript PubMed NCT02099292

Z-BEAM, then auto HSCT

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shimoni et al. 2007	2004-2006	Phase 2
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL)	NR	Randomized Phase 2 (E-esc)	BEAM	Seems to have superior OS
Briones et al. 2013 (GELTAMO Z-BEAM LDCGB)	2008-2010	Phase 2

Patients in SHEBA-07-4466-AN-CTIL had primary induction failure or were chemosensitive to salvage therapy. Patients in GELTAMO Z-BEAM LDCGB had primary induction failure or were refractory to salvage therapy.

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once on day -14, given first

Radioconjugate therapy

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2
• Cytarabine (Ara-C) 200 mg/m² IV every 12 hours on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 (Shimoni et al. 2012) or day +7 (GELTAMO Z-BEAM LDCGB) until engraftment
• Valacyclovir (Valtrex) (dose not specified) for one month (Shimoni et al. 2012)
• Acyclovir (Zovirax) (dose not specified) for one month (Briones et al. 2013)
• Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months (3 months in GELTAMO Z-BEAM LDCGB)

One course

References

1. Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol. 2007 Apr;35(4):534-40. link to original article PubMed
2. SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article contains dosing details in manuscript PubMed NCT00491491
3. GELTAMO Z-BEAM LDCGB: Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernsández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2014 Mar;99(3):505-10. Epub 2013 Oct 25. link to original article contains dosing details in manuscript link to PMC article PubMed EudraCT 2007-003198-22

Maintenance after salvage therapy

Lenalidomide monotherapy

Regimen variant #1, 25 mg 21/28, indefinite

Study	Years of enrollment	Evidence
Ferreri et al. 2017	2009-2015	Phase 2

Preceding treatment

• Rituximab-containing salvage chemotherapy

Targeted therapy

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

28-day cycles

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

Study	Years of enrollment	Evidence
Feldman et al. 2014 (RV-DLBCL-PI-0463)	2010-2012	Phase 1/2, <20 pts

Preceding treatment

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

Targeted therapy

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

28-day cycle for up to 13 cycles (1 year)

References

1. RV-DLBCL-PI-0463: Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. Epub 2014 Mar 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01241734
2. Ferreri AJ, Sassone M, Zaja F, Re A, Spina M, di Rocco A, Fabbri A, Stelitano C, Frezzato M, Rusconi C, Zambello R, Couto S, Ren Y, Arcari A, Bertoldero G, Nonis A, Scarfò L, Calimeri T, Cecchetti C, Chiozzotto M, Govi S, Ponzoni M. Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. Lancet Haematol. 2017 Mar;4(3):e137-e146. Epub 2017 Feb 17. link to original article contains dosing details in abstract PubMed NCT00799513

Rituximab monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gisselbrecht et al. 2010 (CORAL)	2003-2007	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of EFS1

¹Reported efficacy is based on the 2012 update.
Note: Treatment begins on day +28.

Preceding treatment

• BEAM with autologous hematopoietic stem cell transplant

Targeted therapy

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

8-week cycle for 6 cycles

References

1. CORAL: Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00137995
   1. Update: Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, Shpilberg O, Dührsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Brière J, Salles G, Moskowitz CH, Glass B. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012 Dec 20;30(36):4462-9. Epub 2012 Oct 22. link to original article contains dosing details in manuscript link to PMC article PubMed

Relapsed or refractory, further lines of therapy

Note: these are regimens that are generally given with non-curative intent. However, some of these regimens, such as CAR-T therapy, can function as a bridge to consolidation with one of the salvage consolidation regimens, above.

Axicabtagene ciloleucel monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Efficacy
Locke et al. 2017 (ZUMA-1)	2015-2016	Phase 1/2 (RT)	ORR: 83%; CR: 59% Median OS: not reached Median PFS: 6 months Median duration of response: 11 months

Chemotherapy, lymphodepletion

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days -5 to -3 prior to Axicabtagene ciloleucel infusion
• Fludarabine (Fludara) 30 mg/m² IV once per day on days -5 to -3 prior to Axicabtagene ciloleucel infusion

Immunotherapy

• Axicabtagene ciloleucel (Yescarta) target dose of 2 × 10⁶ CAR T cells/kg IV once on day 0

Supportive therapy

• Acetaminophen (Tylenol) 650 mg PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)
• Diphenhydramine (Benadryl) 12.5 mg IV or PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)

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

References

1. ZUMA-1: Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM, Jiang Y, Xue AX, Elias M, Aycock J, Wiezorek J, Go WY. Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017 Jan 4;25(1):285-295. Epub 2017 Jan 4. link to original article link to PMC article PubMed NCT02348216
   1. Update: Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. Epub 2017 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed
   2. Update: Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. Epub 2018 Dec 2. link to original article link to PMC article contains dosing details in manuscript PubMed

Bendamustine monotherapy

Regimen

Study	Years of enrollment	Evidence	Efficacy
Weidmann et al. 2002	NR	Phase 2, <20 pts	ORR: 44%

Chemotherapy

• Bendamustine 120 mg/m² IV once per day on days 1 & 2

21-day cycle for up to 6 cycles

References

1. Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, Mitrou PS. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002 Aug;13(8):1285-9. link to original article contains dosing details in manuscript PubMed

Blinatumomab monotherapy

Regimen

Study	Years of enrollment	Evidence
Viardot et al. 2016 (MT103-208)	2012-2014	Phase 2

Two dosing schemas were evaluated; this is the preferred dosing regimen, per the authors.

Immunotherapy

• Blinatumomab (Blincyto) as follows:
  • Week 1: 9 mcg/day IV continuous infusion
  • Week 2: 28 mcg/day IV continuous infusion
  • Weeks 3 to 8: 112 mcg/day IV continuous infusion

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO 6 to 12 hours before infusion start and dose increases, 20 mg PO 1 hour before infusion start and dose increases, and 8 mg PO three times per day for 2 days following infusion start and dose increases
  • Patients with neurologic symptoms or cytokine release syndrome received 8 mg IV or PO every 8 hours for up to 3 days, with a subsequent taper over 4 days

8-week course

Subsequent treatment

• 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. MT103-208: Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J, Zhang A, Nagorsen D, Bargou RC. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016 Mar 17;127(11):1410-6. Epub 2016 Jan 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01741792

Bendamustine & Rituximab (BR)

BR: Bendamustine & Rituximab R-B: Rituximab & Bendamustine

Regimen variant #1, 6 cycles

Study	Years of enrollment	Evidence
Vacirca et al. 2013 (PI-08904)	2008-2011	Phase 2
Ohmachi et al. 2013 (SymBio 2010001)	2010-2011	Phase 2

Note: Bendamustine was given on days 2 & 3 in SymBio 2010001 and on days 1 & 2 in PI-08904.

Chemotherapy

• Bendamustine 120 mg/m² IV once per day on days 1 & 2 OR on days 2 & 3

Targeted therapy

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

Supportive therapy

• Recommended PCP prophylaxis: Trimethoprim-Sulfamethoxazole (Bactrim DS)
• Recommended VZV prophylaxis: Acyclovir (Zovirax)

21-day cycle for up to 6 cycles

Regimen variant #2, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dang et al. 2017 (B1931008)	2011-2013	Phase 3 (C)	R-INO	Did not meet primary endpoint of OS

Chemotherapy

• Bendamustine 120 mg/m² IV once per day on days 1 & 2

Targeted therapy

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

28-day cycles

References

1. SymBio 2010001: Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013 Jun 10;31(17):2103-9. Epub 2013 May 6. link to original article contains dosing details in manuscript PubMed NCT01118845
2. PI-08904: Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014 Mar;93(3):403-9. Epub 2013 Aug 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00831597
3. B1931008: Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M, Sullivan S, Vandendries E, Tobinai K, Ramchandren R, Hamlin PA, Giné E, Ando K. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018 Aug;182(4):583-586. Epub 2017 Jul 5. link to original article link to PMC article contains dosing details in abstract PubMed NCT01232556
4. GO29365: Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10; 38(2):155-165. Epub 2019 Nov 6. link to original article link to pubmed NCT02257567
   1. Update: Sehn LH, Hertzberg M, Opat S, Herrera AF, Assouline S, Flowers CR, Kim TM, McMillan A, Ozcan M, Safar V, Salles G, Ku G, Hirata J, Chang YM, Musick L, Matasar MJ. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022 Jan 25;6(2):533-543. link to original article link to PMC article PubMed

Bendamustine & Rituximab (BR) & Polatuzumab vedotin

BR & Polatuzumab vedotin: Bendamustine, Rituximab, Polatuzumab vedotin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sehn et al. 2019 (GO29365)	2014-2016	Randomized Phase 2 (E-RT-esc)	BR	Seems to have superior ORR

Chemotherapy

• Bendamustine as follows:
  • Cycle 1: 90 mg/m² IV once per day on days 2 & 3
  • Cycles 2 to 6: 90 mg/m² IV once per day on days 1 & 2

Targeted therapy

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

Antibody-drug conjugate therapy

• Polatuzumab vedotin (Polivy) as follows:
  • Cycle 1: 1.8 mg/kg IV over 90 minutes once on day 2
  • Cycles 2 to 6: 1.8 mg/kg IV over 90 minutes once on day 1

References

1. GO29365: Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10; 38(2):155-165. Epub 2019 Nov 6. link to original article link to pubmed NCT02257567
   1. Update: Sehn LH, Hertzberg M, Opat S, Herrera AF, Assouline S, Flowers CR, Kim TM, McMillan A, Ozcan M, Safar V, Salles G, Ku G, Hirata J, Chang YM, Musick L, Matasar MJ. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022 Jan 25;6(2):533-543. link to original article link to PMC article PubMed

Brentuximab vedotin monotherapy

Regimen

Study	Years of enrollment	Evidence
Jacobsen et al. 2015 (SGN35-012)	2011-2013	Phase 2

Jacobsen et al. 2015 treated patients with CD30+ non-Hodgkin lymphoma, as determined by IHC; the 2016 update describes a subgroup with undetectable CD30.

Antibody-drug conjugate therapy

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

21-day cycles

References

1. SGN35-012: Jacobsen ED, Sharman JP, Oki Y, Advani RH, Winter JN, Bello CM, Spitzer G, Palanca-Wessels MC, Kennedy DA, Levine P, Yang J, Bartlett NL. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015 Feb 26;125(9):1394-402. Epub 2015 Jan 8. link to original article contains dosing details in manuscript PubMed NCT01421667
   1. Update: Bartlett NL, Smith MR, Siddiqi T, Advani RH, O'Connor OA, Sharman JP, Feldman T, Savage KJ, Shustov AR, Diefenbach CS, Oki Y, Palanca-Wessels MC, Uttarwar M, Li M, Yang J, Jacobsen ED. Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leuk Lymphoma. 2017 Jul;58(7):1607-1616. Epub 2016 Nov 20. link to original article PubMed

Etoposide monotherapy

Regimen variant #1, IV (3 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Chemotherapy

• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 3

28-day cycle for up to 6 cycles

Regimen variant #2, IV (5 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3, <20 pts in this arm (C)	Pixantrone	Seems to have inferior CR/CRu rate
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Chemotherapy

• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

28-day cycle for up to 6 cycles

Regimen variant #3, PO (10 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Chemotherapy

• Etoposide (Vepesid) 50 mg/m² PO once per day on days 1 to 10

28-day cycle for up to 6 cycles

Regimen variant #4, PO (14 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Chemotherapy

• Etoposide (Vepesid) 50 mg/m² PO once per day on days 1 to 14

28-day cycle for up to 6 cycles

Regimen variant #5, PO (21 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 1992	1988-1989	Phase 2
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3, <20 pts in this arm (C)	Pixantrone	Seems to have inferior CR/CRu rate
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

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

Chemotherapy

• Etoposide (Vepesid) 50 mg/m² PO once per day on days 1 to 21

28-day cycle for up to 6 cycles

References

1. Hainsworth JD, Johnson DH, Greco FA. Chronic etoposide schedules in the treatment of non-Hodgkin's lymphoma. Semin Oncol. 1992 Dec;19(6 Suppl 14):13-8. link to original article PubMed
2. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530
3. DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains dosing details in supplement PubMed EudraCT 2009-013483-38

Everolimus monotherapy

Regimen

Study	Years of enrollment	Evidence
Witzig et al. 2011	2005-2008	Phase 2

Targeted therapy

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

Supportive therapy

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

28-day cycles

References

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

Everolimus & Rituximab

Regimen

Study	Years of enrollment	Evidence
Barnes et al. 2013 (MGH 09-002)	2009-2010	Phase 2

Targeted therapy

• Everolimus (Afinitor) as follows:
  • Cycle 1: 5 mg PO once per day on days 1 to 14, then 10 mg PO once per day on days 15 to 28
  • Cycles 2 to 6: 10 mg PO once per day
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycles 2 to 6: 375 mg/m² IV once on day 1

28-day cycle for 6 cycles

Subsequent treatment

• Responders had the option of continuing everolimus alone for another 6 months

References

1. MGH 09-002: Barnes JA, Jacobsen E, Feng Y, Freedman A, Hochberg EP, LaCasce AS, Armand P, Joyce R, Sohani AR, Rodig SJ, Neuberg D, Fisher DC, Abramson JS. Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma. Haematologica. 2013 Apr;98(4):615-9. Epub 2012 Nov 9. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00869999

Gemcitabine monotherapy

Regimen variant #1, bi-weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 15

28-day cycle for up to 6 cycles

Regimen variant #2, 3 out of 4 weeks x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1, 8, 15

28-day cycle for up to 6 cycles

Regimen variant #3, indefinite 3 out of 4 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fosså et al. 1999	1995-1997	Phase 2
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3, <20 pts in this arm (C)	Pixantrone	Seems to have inferior CR/CRu rate

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

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1250 mg/m² IV over 30 minutes once per day on days 1, 8, 15
  • Fosså et al. 1999, subsequent cycles (if no hematologic or nonhematologic toxicities): Optional increase to 1500 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycle for up to 6 cycles (PIX301) or indefinitely (Fosså et al. 1999)

References

1. Fosså A, Santoro A, Hiddemann W, Truemper L, Niederle N, Buksmaui S, Bonadonna G, Seeber S, Nowrousian MR. Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3786-92. link to original article contains dosing details in manuscript PubMed
2. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530
3. DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains dosing details in supplement PubMed EudraCT 2009-013483-38

Gemcitabine & Rituximab

R-G: Rituximab & Gemcitabine

Regimen variant #1, 6 cycles maximum

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pettengell et al. 2019 (PIX306)	2011-2018	Phase 3 (C)	Pixantrone & Rituximab	Did not meet primary endpoint of PFS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

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

28-day cycle for up to 6 cycles

Regimen variant #2, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dang et al. 2017 (B1931008)	2011-2013	Phase 3 (C)	R-INO	Did not meet primary endpoint of OS

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 2 onwards: 375 mg/m² IV once on day 1

28-day cycles

References

1. B1931008: Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M, Sullivan S, Vandendries E, Tobinai K, Ramchandren R, Hamlin PA, Giné E, Ando K. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018 Aug;182(4):583-586. Epub 2017 Jul 5. link to original article link to PMC article contains dosing details in abstract PubMed NCT01232556
2. PIX306: Pettengell R, Długosz-Danecka M, Andorsky D, Belada D, Georgiev P, Quick D, Singer JW, Singh SB, Pallis A, Egorov A, Salles G. Pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma not eligible for stem cell transplantation: a phase 3, randomized, multicentre trial (PIX306). Br J Haematol. 2020 Jan;188(2):240-248. Epub 2019 Dec 27. link to original article contains dosing details in abstract PubMed NCT01321541

GVD

GVD: Gemcitabine, Vinorelbine, Doxil (Pegylated liposomal doxorubicin)

Regimen

Study	Evidence
Bai et al. 2013	Retrospective

Chemotherapy

• Gemcitabine (Gemzar) 800 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 15 mg/m² IV once on day 1
• Pegylated liposomal doxorubicin (Doxil) 20 mg/m² IV once on day 1

14-day cycles

References

1. Retrospective: Bai B, Huang HQ, Cai QQ, Wang XX, Cai QC, Lin ZX, Gao Y, Xia Y, Bu Q, Guo Y. Promising long-term outcome of gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule as salvage regimen for patients with previously heavily treated Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma. Med Oncol. 2013 Mar;30(1):350. Epub 2013 Jan 18. link to original article contains dosing details in abstract PubMed

Ibritumomab tiuxetan protocol

Regimen

Study	Years of enrollment	Evidence
Morschhauser et al. 2007	2001-2003	Phase 2

To be completed

Radioconjugate therapy

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin)

References

1. Morschhauser F, Illidge T, Huglo D, Martinelli G, Paganelli G, Zinzani PL, Rule S, Liberati AM, Milpied N, Hess G, Stein H, Kalmus J, Marcus R. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood. 2007 Jul 1;110(1):54-8. Epub 2007 Mar 26. link to original article PubMed

Ibrutinib monotherapy

Regimen

Study	Years of enrollment	Evidence
Wilson et al. 2015 (PCYC-1106-CA)	2010-2012	Phase 2

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

Targeted therapy

• Ibrutinib (Imbruvica) 560 mg PO once per day

Continued indefinitely

References

1. PCYC-1106-CA: Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, Lih CJ, Williams PM, Shaffer AL, Gerecitano J, de Vos S, Goy A, Kenkre VP, Barr PM, Blum KA, Shustov A, Advani R, Fowler NH, Vose JM, Elstrom RL, Habermann TM, Barrientos JC, McGreivy J, Fardis M, Chang BY, Clow F, Munneke B, Moussa D, Beaupre DM, Staudt LM. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. Epub 2015 Jul 20. link to original article PubMed NCT00849654; NCT01325701

Ifosfamide monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Case et al. 1991 (CALGB 8552)	NR	Phase 2
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3, <20 pts in this arm (C)	Pixantrone	Seems to have inferior CR/CRu rate

Dose & schedule is as given in Pettengell et al. 2012. CALGB 8552 used a different dose & schedule. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Ifosfamide (Ifex) 3000 mg/m² IV once per day on days 1 & 2

Supportive therapy

• Mesna (Mesnex) dose not specified

28-day cycle for up to 6 cycles

References

1. CALGB 8552: Case DC Jr, Anderson J, Ervin TJ, Gottlieb A. Phase II trial of ifosfamide and mesna in previously treated patients with non-Hodgkin's lymphoma: Cancer and Leukemia Group B study 8552. Hematol Oncol. 1991 Jul-Oct;9(4-5):189-96. link to original article 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. link to original article PubMed
3. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530

Lenalidomide monotherapy

Regimen variant #1, low dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (E-switch-ooc)	Investigator's choice of: 1. Etoposide 2. Gemcitabine 3. Oxaliplatin 4. Rituximab	Might have superior ORR

This dose was intended for patients with CrCl at least 30 but less than 60 mL/min/1.73m².

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

28-day cycles

Regimen variant #2, normal dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wiernik et al. 2008 (CC-5013-NHL-002)	2005-2006	Phase 2		ORR: 35%
Witzig et al. 2011 (NHL-003)	2006-2008	Phase 2		ORR: 28%
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (E-switch-ooc)	Investigator's choice of: 1. Etoposide 2. Gemcitabine 3. Oxaliplatin 4. Rituximab	Might have superior ORR

Targeted therapy

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

28-day cycles

References

1. CC-5013-NHL-002: Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, Lam W, McBride K, Wride K, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Habermann TM. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2008 Oct 20;26(30):4952-7. Epub 2008 Jul 7. link to original article contains dosing details in manuscript PubMed NCT00179660
2. NHL-003: Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol. 2011 Jul;22(7):1622-7. Epub 2011 Jan 12. link to original article contains dosing details in manuscript PubMed NCT00413036
3. DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains dosing details in manuscript PubMed EudraCT 2009-013483-38

Lenalidomide & Rituximab (R²)

Regimen variant #1, indefinite

Study	Years of enrollment	Evidence
Wang et al. 2013 (MDACC 2005-0461)	2008-2011	Phase 2

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, 4 cycles

Study	Years of enrollment	Evidence
Zinzani et al. 2011 (REVLIRIT01)	2009	Phase 2

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 21

28-day cycle for 4 cycles

Subsequent treatment

• SD or better: Lenalidomide maintenance

References

1. REVLIRIT01: 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 dosing details in manuscript PubMed NCT00968331
   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. MDACC 2005-0461: Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013 Sep;27(9):1902-9. Epub 2013 Apr 2. link to original article contains dosing details in manuscript PubMed NCT00294632

Lenalidomide & Tafasitamab

Regimen

Study	Years of enrollment	Evidence
Salles et al. 2020 (L-MIND)	2016-2017	Phase 2 (RT)

Targeted therapy

• Lenalidomide (Revlimid) as follows:
  • Cycles 1 to 12: 25 mg PO once per day on days 1 to 21
• Tafasitamab (Monjuvi) as follows:
  • Cycle 1: 12 mg/kg IV over 2 hours once per day on days 1, 4, 8, 15, 22
  • Cycles 2 & 3: 12 mg/kg IV over 2 hours once per day on days 1, 8, 15, 22
  • Cycle 4 onwards: 12 mg/kg IV over 2 hours once per day on days 1 & 15

28-day cycles

References

1. L-MIND: Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM, Nagy Z, Obr A, Gaidano G, André M, Kalakonda N, Dreyling M, Weirather J, Dirnberger-Hertweck M, Ambarkhane S, Fingerle-Rowson G, Maddocks K. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020 Jul;21(7):978-988. Epub 2020 Jun 5. link to original article contains dosing details in manuscript PubMed NCT02399085
   1. Update: Duell J, Maddocks KJ, González-Barca E, Jurczak W, Liberati AM, De Vos S, Nagy Z, Obr A, Gaidano G, Abrisqueta P, Kalakonda N, André M, Dreyling M, Menne T, Tournilhac O, Augustin M, Rosenwald A, Dirnberger-Hertweck M, Weirather J, Ambarkhane S, Salles G. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021 Sep 1;106(9):2417-2426. link to original article link to PMC article PubMed

Lisocabtagene maraleucel monotherapy

Regimen

Study	Years of enrollment	Evidence
Abramson et al. 2020 (TRANSCEND NHL-001)	2016-2019	Phase 1 (RT)

Immunotherapy

• Lisocabtagene maraleucel (Breyanzi)

References

1. TRANSCEND NHL-001: Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson TM, Garcia J, Kostic A, Mallaney M, Ogasawara K, Newhall K, Kim Y, Li D, Siddiqi T. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020 Sep 19;396(10254):839-852. Epub 2020 Sep 1. link to original article PubMed NCT02631044

Loncastuximab tesirine monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Caimi et al. 2021 (LOTIS-2)	2018-2019	Phase 2 (RT)

Antibody-drug conjugate therapy

• Loncastuximab tesirine (Zynlonta) as follows:
  • Cycles 1 & 2: 0.15 mg/kg IV over 30 minutes once on day 1
  • Cycle 3 onwards: 0.075 mg/kg IV over 30 minutes once on day 1

Supportive therapy

• Dexamethasone (Decadron) 4 mg IV or PO twice per day on days -1 to 2 (3 days total)

21-day cycles for up to 18 cycles (1 year)

References

1. LOTIS-2: Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800. Epub 2021 May 11. link to original article contains dosing details in abstract PubMed NCT03589469

Mitoxantrone monotherapy

Regimen

Study	Years of enrollment	Evidence
Bajetta et al. 1988a	NR in abstract	Phase 2

Chemotherapy

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

21-day cycles

References

1. Bajetta E, Buzzoni R, Valagussa P, Bonadonna G. Mitoxantrone: an active agent in refractory non-Hodgkin's lymphomas. Am J Clin Oncol. 1988 Apr;11(2):100-3. contains dosing details in abstract PubMed
2. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530

Obinutuzumab monotherapy

Regimen

Study	Years of enrollment	Evidence
Salles et al. 2012 (GAUGUIN)	2008-2009	Phase 1/2

Note: this is the phase II dosing reported in Morschhauser et al. 2013.

Targeted therapy

• 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 therapy

• Acetaminophen (Tylenol) or paracetamol 650 to 1000 mg PO once per infusion, 30 minutes prior to Obinutuzumab (Gazyva)
• "An antihistamine" once per infusion, 30 minutes prior to Obinutuzumab (Gazyva)
  • If there were no infusion-related reactions (IRRs) requiring medication or infusion interruption, antihistamine could be omitted for subsequent infusions
• Premedication with corticosteroids recommended for patients at high risk of infusion-related reactions (IRRs)
• Use of G-CSF allowed for severe neutropenia
• Antibiotic prophylaxis allowed

21-day cycle for 8 cycles

References

1. GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed NCT00517530
   1. Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed
   2. Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed
   3. Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article contains dosing details in manuscript PubMed

Ofatumumab monotherapy

Regimen

Study	Years of enrollment	Evidence
Coiffier et al. 2013 (415 Study)	2007-NR	Phase 2

Targeted therapy

• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
  • Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22

Supportive therapy

• Acetaminophen (Tylenol) (or equivalent) 1000 mg PO once per day on days 1, 8, 15, 22; 30 minutes to 2 hours prior to Ofatumumab (Arzerra)
• Cetirizine (Zyrtec) (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22; 30 minutes to 2 hours prior to Ofatumumab (Arzerra)
• Prednisolone (Millipred) (or equivalent) 100 mg (route not specified) once per day on days 1 & 8; 30 minutes to 2 hours prior to Ofatumumab (Arzerra) for first 2 infusions, only

28-day cycle for 2 cycles

References

1. 415 Study: Coiffier B, Radford J, Bosly A, Martinelli G, Verhoef G, Barca G, Davies A, Decaudin D, Gallop-Evans E, Padmanabhan-Iyer S, Van Eygen K, Wu KL, Gupta IV, Lin TS, Goldstein N, Jewell RC, Winter P, Lisby S; 415 study investigators. A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma. Br J Haematol. 2013 Nov;163(3):334-42. Epub 2013 Aug 23. link to original article contains dosing details in manuscript PubMed NCT00622388

Oxaliplatin monotherapy

Regimen variant #1, 100 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Germann et al. 1999	1988-1994	Phase 2, <20 pts in this subgroup
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3, <20 pts in this arm (C)	Pixantrone	Seems to have inferior CR/CRu rate
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Germann et al. give a range of 100 to 130 mg/m². To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 1

21-day cycles (maximum of 6 cycles in PIX301 & DLC-001)

Regimen variant #2, 130 mg/m²

Study	Years of enrollment	Evidence	Efficacy
Germann et al. 1999	1988-1994	Phase 2, <20 pts in this subgroup
Oki et al. 2005	2001-2003	Phase 2	ORR: 27% (95% CI, 13–47)

Germann et al. give a range of 100 to 130 mg/m².

Chemotherapy

• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycles

References

1. Germann N, Brienza S, Rotarski M, Emile JF, Di Palma M, Musset M, Reynes M, Soulié P, Cvitkovic E, Misset JL. Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients. Ann Oncol. 1999 Mar;10(3):351-4. link to original article contains dosing details in manuscript 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. 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 dosing details in manuscript PubMed
4. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530
5. DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains dosing details in supplement PubMed EudraCT 2009-013483-38

Panobinostat monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Assouline et al. 2016 (Q-CROC-02)	2010-2013	Randomized Phase 2 (E-de-esc)	Panobinostat & Rituximab	Did not meet primary endpoint of ORR

Note: patients had a median of 2 prior treatments (range 1-8).

Targeted therapy

• Panobinostat (Farydak) 30 mg PO three times per week (e.g., MWF)

21-day cycles

References

1. Q-CROC-02: Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, Tosikyan A, Kukreti V, Kezouh A, Petrogiannis-Haliotis T, Albuquerque M, Fornika D, Alamouti S, Froment R, Greenwood CM, Oros KK, Camglioglu E, Sharma A, Christodoulopoulos R, Rousseau C, Johnson N, Crump M, Morin RD, Mann KK. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016 Jul 14;128(2):185-94. Epub 2016 May 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01238692

Panobinostat & Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Assouline et al. 2016 (Q-CROC-02)	2010-2013	Randomized Phase 2, <20 pts (E-esc)	Panobinostat	Did not meet primary endpoint of ORR

Note: patients had a median of 3 prior treatments (range 2-9).

Targeted therapy

• Panobinostat (Farydak) 30 mg PO three times per week (e.g., MWF)
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

21-day cycles

References

1. Q-CROC-02: Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, Tosikyan A, Kukreti V, Kezouh A, Petrogiannis-Haliotis T, Albuquerque M, Fornika D, Alamouti S, Froment R, Greenwood CM, Oros KK, Camglioglu E, Sharma A, Christodoulopoulos R, Rousseau C, Johnson N, Crump M, Morin RD, Mann KK. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016 Jul 14;128(2):185-94. Epub 2016 May 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01238692

Pixantrone monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3 (E-switch-ic)	Investigator's choice of: 1. Etoposide 2. Gemcitabine 3. Ifosfamide 4. Mitoxantrone 5. Oxaliplatin 6. Vinorelbine	Seems to have superior CR/CRu rate

Chemotherapy

• Pixantrone (Pixuvri) 85 mg/m² IV once per day on days 1, 8, 15

28-day cycle for up to 6 cycles

References

1. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530
   1. Post-hoc analysis: Pettengell R, Sebban C, Zinzani PL, Derigs HG, Kravchenko S, Singer JW, Theocharous P, Wang L, Pavlyuk M, Makhloufi KM, Coiffier B. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016 Sep;174(5):692-9. Epub 2016 Apr 26. link to original article link to PMC article PubMed

Rituximab monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Coiffier et al. 1998	1996-1997	Randomized Phase 2 (E-de-esc)	Rituximab; higher-dose	Did not meet primary endpoint of ORR
Czuczman et al. 2017 (DLC-001)	2009-2013	Phase 2/3 (C)	Lenalidomide	Might have inferior ORR

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycles 4, 6, 8, 10: 375 mg/m² IV once on day 1

28-day cycle for 10 cycles (8 doses total)

References

1. Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feuring-Buske M, Radford JA, Capdeville R, Diehl V, Reyes F. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998 Sep 15;92(6):1927-32. link to original article PubMed
2. DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains dosing details in supplement PubMed EudraCT 2009-013483-38

R-BL

R-BL: Rituximab, Bendamustine, Lenalidomide

Regimen

Study	Years of enrollment	Evidence	Efficacy
Hitz et al. 2016 (SAKK 38/08)	NR	Phase 2	ORR: 61% (95% CI 45-76%)

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 2

28-day cycle for 6 cycles

References

1. SAKK 38/08: 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 dosing details in abstract PubMed NCT00987493

R-CVEP

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

Regimen

Study	Years of enrollment	Evidence
Straus et al. 2014 (MSK 08-045)	2008-2012	Phase 2

The MTD for vorinostat was 300 mg in this phase I/II trial.

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Vorinostat (Zolinza) 300 mg PO once per day on days 1 to 10

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once per day on days 1 & 8
• Etoposide (Vepesid) 70 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 10

28-day cycle for 6 cycles

References

1. MSK 08-045: Straus DJ, Hamlin PA, Matasar MJ, Lia Palomba M, Drullinsky PR, Zelenetz AD, Gerecitano JF, Noy A, Hamilton AM, Elstrom R, Wegner B, Wortman K, Cella D. Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma not eligible for autologous stem cell transplantation. Br J Haematol. 2015 Mar;168(5):663-70. Epub 2014 Oct 15. link to original article contains dosing details in abstract PubMed NCT00667615

R-GemOx

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

Regimen variant #1, 14-day cycles

Study	Years of enrollment	Evidence
El Gnaoui et al. 2007	2002-2005	Phase 2
Mounier et al. 2013	2003-2009	Phase 2

Targeted therapy

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV at fixed dose rate over 100 minutes once on day 2
• Oxaliplatin (Eloxatin) 100 mg/m² IV over 2 hours once on day 2

Supportive therapy

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

14-day cycle for up to 8 cycles

Regimen variant #2, 21-day cycles

Study	Years of enrollment	Evidence
López et al. 2008	NR in abstract	Phase 2

Targeted therapy

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 1

21-day cycle for 6 to 8 cycles

References

1. El Gnaoui T, Dupuis J, Belhadj K, Jais JP, Rahmouni A, Copie-Bergman C, Gaillard I, Diviné M, Tabah-Fisch I, Reyes F, Haioun C. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007 Aug;18(8):1363-8. Epub 2007 May 11. link to original article contains dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT00169195

Selinexor monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Kalakonda et al. 2020 (SADAL)	2015-2019	Phase 2b (RT)

Targeted therapy

• Selinexor (Xpovio) 60 mg PO once per day on days 1 & 3

7-day cycles

References

1. SADAL: Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, Casasnovas O, Hamad N, Zijlstra JM, Bakhshi S, Bouabdallah R, Choquet S, Gurion R, Hill B, Jaeger U, Sancho JM, Schuster M, Thieblemont C, De la Cruz F, Egyed M, Mishra S, Offner F, Vassilakopoulos TP, Warzocha K, McCarthy D, Ma X, Corona K, Saint-Martin JR, Chang H, Landesman Y, Joshi A, Wang H, Shah J, Shacham S, Kauffman M, Van Den Neste E, Canales MA. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020 Jul;7(7):e511-e522. link to original article contains dosing details in abstract PubMed NCT02227251

Temsirolimus monotherapy

Regimen

Study	Years of enrollment	Evidence	Efficacy
Smith et al. 2010 (NCI-6199)	2004-NR	Phase 2	ORR: 28%

Targeted therapy

• Temsirolimus (Torisel) 25 mg IV over 30 minutes once per day on days 1, 8, 15, 22

28-day cycle for up to 6 cycles

References

1. NCI-6199: 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 dosing details in manuscript link to PMC article PubMed NCT00290472

Tisagenlecleucel monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Efficacy
Schuster et al. 2017 (UPCC 13413)	2014-2016	Phase 2
Schuster et al. 2018 (JULIET)	2015-2017	Phase 2 (RT)	ORR: 59% (95% CI, 44-72)

The range given is the FDA-recommended dose used in JULIET.

Preceding treatment

• Lymphodepleting therapy with FC or Bendamustine

Immunotherapy

• Tisagenlecleucel (Kymriah) 0.6 to 6 x 10⁸ CTL019 transduced viable T-cells IV once on day 0

One course

References

1. UPCC 13413: Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, Wasik M, Levine BL, Lacey SF, Melenhorst JJ, Porter DL, June CH. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28;377(26):2545-2554. Epub 2017 Dec 10. link to original article link to PMC article PubMed NCT02030834
2. JULIET: Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. Epub 2018 Dec 1. link to original article PubMed NCT02445248
   1. Update: Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Bishop MR, Damon LE, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu JM, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradini P, Martinez-Prieto M, Han X, Tiwari R, Salles G, Maziarz RT. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1403-1415. Epub 2021 Sep 10. link to original article PubMed

TTR

TTR: Taxol (Paclitaxel), Topotecan, Rituximab

Regimen

Study	Years of enrollment	Evidence
Westin et al. 2014	1999-2003	Phase 2

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV once on day 2
• Topotecan (Hycamtin) 1 mg/m² IV once per day on days 2 to 6

Targeted therapy

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

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 7 until neutrophil recovery
• Dexamethasone (Decadron) 20 mg IV once on day 2; 30 minutes prior to Paclitaxel (Taxol)
• Diphenhydramine (Benadryl) 50 mg IV once on day 2; 30 minutes prior to Paclitaxel (Taxol)

21-day cycle for up to 6 cycles

References

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 dosing details in manuscript link to PMC article PubMed

Vinorelbine monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Balzarotti et al. 1996	1992-1994	Non-randomized, <20 pts in this subgroup
Pettengell et al. 2012 (PIX301)	2004-2008	Phase 3, <20 pts in this arm (C)	Pixantrone	Seems to have inferior CR/CRu rate

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

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for up to 6 cycles

References

1. Balzarotti M, Santoro A, Tondini C, Fornier M, Bonadonna G. Activity of single agent vinorelbine in pretreated non-Hodgkin's lymphoma. Ann Oncol. 1996 Nov;7(9):970-2. link to original article contains dosing details in manuscript 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. link to original article PubMed
3. PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains dosing details in manuscript PubMed NCT00088530
   1. Post-hoc analysis: Pettengell R, Sebban C, Zinzani PL, Derigs HG, Kravchenko S, Singer JW, Theocharous P, Wang L, Pavlyuk M, Makhloufi KM, Coiffier B. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016 Sep;174(5):692-9. Epub 2016 Apr 26. link to original article link to PMC article PubMed

Maintenance after further lines of therapy

Lenalidomide monotherapy

Regimen

Study	Years of enrollment	Evidence
Zinzani et al. 2011 (REVLIRIT01)	2009	Phase 2

Preceding treatment

• Lenalidomide & Rituximab x 4

Targeted therapy

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

28-day cycle for 9 cycles

References

1. REVLIRIT01: 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 dosing details in manuscript PubMed NCT00968331
   1. Update: Zinzani PL, Pellegrini C, Derenzini E, Argnani L, Pileri S. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients. Hematol Oncol. 2013 Dec;31(4):223-4. Epub 2013 Apr 26. link to original article PubMed

Response criteria

• Lugano Classification criteria (2014) link to PMC article PubMed
• International Harmonization Project on Lymphoma revised criteria (2007) PubMed
• NCI Sponsored International Working Group criteria (1999) PubMed

Prognosis

IPI and age-adjusted IPI (1993)

To be completed

1. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30;329(14):987-94. link to original article PubMed

Revised International Prognostic Index, R-IPI (2007)

To be completed

1. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007 Mar 1;109(5):1857-61. Epub 2006 Nov 14. link to original article PubMed

CNS-IPI (2016)

Risk factors

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

Risk stratification

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

References

1. Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, Glass B, Scott DW, Gascoyne RD, Connors JM, Ziepert M, Pfreundschuh M, Loeffler M, Savage KJ. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016 Sep 10;34(26):3150-3156. Epub 2016 Jul 5. link to original article PubMed

Investigational agents

These are drugs under study with at least some promising results for this disease.

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