Classical Hodgkin lymphoma

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 Tarsheen Sethi, MD, MSCI
Yale University
New Haven, CT, USA
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Are you looking for a regimen 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.

  • We have moved How I Treat articles to a dedicated page.

Note: certain regimens can be found on dedicated pages:

82 regimens on this page
129 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASBMT

ESMO

NCCN

SITC

Untreated, early-stage favorable (ESF)

Note: the definition of early stage favorable varies across organizations, e.g., EORTC, GHSG, NCIC, and NCCN; see original definitions used in the trials for details.

ABVD

ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Example orders

Regimen variant #1, 2 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Engert et al. 2007 (GHSG HD7) 1993-1998 Phase 3 (E-esc) No chemotherapy Superior FFTF
Engert et al. 2010 (GHSG HD10) 1998-2003 Phase 3 (E-de-esc) ABVD x 4 Did not meet primary endpoint of FFTF
Behringer et al. 2014 (GHSG HD13) 2003-2009 Phase 3 (C) 1. ABV Superior FFTF
2. AV Superior FFTF
3. AVD Might have superior FFTF
Fuchs et al. 2019 (GHSG HD16) 2009-2015 Non-randomized part of phase 3 RCT

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • GHSG HD7: EFRT consolidation
  • GHSG HD10: IFRT x 2000 cGy versus IFRT x 3000 cGy consolidation
  • GHSG HD13: IFRT x 3000 cGy consolidation
  • GHSG HD16, PET-negative: IFRT x 2000 cGy consolidation versus no further treatment
  • GHSG HD16, PET-positive: IFRT x 2000 cGy consolidation


Regimen variant #2, 2 cycles with response adaptation

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10 F) 2006-2009 Phase 3 (E-switch-ooc) See link See link
Straus et al. 2018 (CALGB 50604) 2010-2013 Non-randomized

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • EORTC/LYSA/FIL H10 F, negative interim PET-CT (1 or 2 points on the 5-point Deauville scale): ABVD continuation x 2 (4 total) versus ABVD continuation x 1 (3 total), then INRT consolidation
  • EORTC/LYSA/FIL H10 F, positive interim PET-CT: eBEACOPP salvage, then INRT consolidation
  • CALGB 50604, negative interim PET-CT (1 to 3 points on the 5-point Deauville scale): ABVD continuation x 2 (4 total)
  • CALGB 50604, positive interim PET-CT: eBEACOPP salvage x 2, then IFRT x 3060 cGy consolidation


Regimen variant #3, 3 cycles with response adaptation

Study Dates of enrollment Evidence
Radford et al. 2015 (UK NCRI RAPID) 2003-2010 Non-randomized part of phase 3 RCT

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment


Regimen variant #4, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 2004 1990-1996 Non-randomized part of phase 3 RCT
Meyer et al. 2005 (NCIC-CTG/ECOG HD.6 F) 1994-2002 Phase 3 (E-switch-ooc) STNI Seems to have superior OS1 (primary endpoint)
OS144: 94% vs 87%
(HR 0.50, 95% CI 0.25-0.99)
Engert et al. 2010 (GHSG HD10) 1998-2003 Phase 3 (C) ABVD x 2 Did not meet primary endpoint of FFTF

1Reported efficacy for NCIC-CTG/ECOG HD.6 F is based on the 2011 update.

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

  • Bonadonna et al. 2004: IFRT versus STNI consolidation
  • GHSG HD10: IFRT x 2000 cGy versus IFRT x 3000 cGy consolidation

References

  1. Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, Valagussa P. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol. 2004 Jul 15;22(14):2835-41. Epub 2004 Jun 15. link to original article contains dosing details in abstract PubMed
  2. NCIC-CTG/ECOG HD.6 F: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Bezjak A, Wells WA, Burns BF, Winter JN, Horning SJ, Dar AR, Djurfeldt MS, Ding K, Shepherd LE; National Cancer Institute of Canada Clinical Trials Group; ECOG. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 Jul 20;23(21):4634-42. Epub 2005 Apr 18. link to original article PubMed NCT00002561
    1. Update: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN, Horning SJ, Dar AR, Shustik C, Stewart DA, Crump M, Djurfeldt MS, Chen BE, Shepherd LE; NCIC Clinical Trials Group; ECOG. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med. 2012 Feb 2;366(5):399-408. Epub 2011 Dec 11. link to original article link to PMC article contains dosing details in abstract PubMed
  3. GHSG HD7: Engert A, Franklin J, Eich HT, Brillant C, Sehlen S, Cartoni C, Herrmann R, Pfreundschuh M, Sieber M, Tesch H, Franke A, Koch P, de Wit M, Paulus U, Hasenclever D, Loeffler M, Müller RP, Müller-Hermelink HK, Dühmke E, Diehl V. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol. 2007 Aug 10;25(23):3495-502. Epub 2007 Jul 2. link to original article contains dosing details in abstract PubMed
    1. Pooled update: Sasse S, Bröckelmann PJ, Goergen H, Plütschow A, Müller H, Kreissl S, Buerkle C, Borchmann S, Fuchs M, Borchmann P, Diehl V, Engert A. Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 trials. J Clin Oncol. 2017 Jun 20;35(18):1999-2007. Epub 2017 Apr 18. link to original article PubMed
  4. GHSG HD10: Engert A, Plütschow A, Eich HT, Lohri A, Dörken B, Borchmann P, Berger B, Greil R, Willborn KC, Wilhelm M, Debus J, Eble MJ, Sökler M, Ho A, Rank A, Ganser A, Trümper L, Bokemeyer C, Kirchner H, Schubert J, Král Z, Fuchs M, Müller-Hermelink HK, Müller RP, Diehl V. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med. 2010 Aug 12;363(7):640-52. link to original article PubMed NCT00265018
    1. Pooled subgroup analysis: Böll B, Görgen H, Fuchs M, Pluetschow A, Eich HT, Bargetzi MJ, Weidmann E, Junghanß C, Greil R, Scherpe A, Schmalz O, Eichenauer DA, von Tresckow B, Rothe A, Diehl V, Engert A, Borchmann P. ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol. 2013 Apr 20;31(12):1522-9. Epub 2013 Mar 18. link to original article PubMed
    2. Pooled subgroup analysis: Böll B, Goergen H, Behringer K, Bröckelmann PJ, Hitz F, Kerkhoff A, Greil R, von Tresckow B, Eichenauer DA, Bürkle C, Borchmann S, Fuchs M, Diehl V, Engert A, Borchmann P. Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials. Blood. 2016 May 5;127(18):2189-92. Epub 2016 Feb 1. link to original article PubMed
    3. Pooled update: Sasse S, Bröckelmann PJ, Goergen H, Plütschow A, Müller H, Kreissl S, Buerkle C, Borchmann S, Fuchs M, Borchmann P, Diehl V, Engert A. Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 trials. J Clin Oncol. 2017 Jun 20;35(18):1999-2007. Epub 2017 Apr 18. link to original article PubMed
  5. EORTC/LYSA/FIL H10: Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains dosing details in abstract PubMed NCT00433433
    1. Update: André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. link to original article PubMed
    2. Update: Federico M, Fortpied C, Stepanishyna Y, Gotti M, van der Maazen R, Cristinelli C, Re A, Plattel W, Lazarovici J, Merli F, Specht L, Schiano de Colella JM, Hutchings M, Versari A, Edeline V, Stamatoulas A, Girinsky T, Ricardi U, Aleman B, Meulemans B, Tonino S, Raemaekers J, André M. Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma. J Clin Oncol. 2024 Jan 1;42(1):19-25. Epub 2023 Nov 15. link to original article link to PMC article PubMed
  6. GHSG HD13: Behringer K, Goergen H, Hitz F, Zijlstra JM, Greil R, Markova J, Sasse S, Fuchs M, Topp MS, Soekler M, Mathas S, Meissner J, Wilhelm M, Koch P, Lindemann HW, Schalk E, Semrau R, Kriz J, Vieler T, Bentz M, Lange E, Mahlberg R, Hassler A, Vogelhuber M, Hahn D, Mezger J, Krause SW, Skoetz N, Böll B, von Tresckow B, Diehl V, Hallek M, Borchmann P, Stein H, Eich H, Engert A; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015 Apr 11;385(9976):1418-27. Epub 2014 Dec 22. Erratum in: Lancet. 2015 Apr 11;385(9976):1396. link to original article PubMed ISRCTN63474366
    1. Pooled subgroup analysis: Böll B, Goergen H, Behringer K, Bröckelmann PJ, Hitz F, Kerkhoff A, Greil R, von Tresckow B, Eichenauer DA, Bürkle C, Borchmann S, Fuchs M, Diehl V, Engert A, Borchmann P. Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials. Blood. 2016 May 5;127(18):2189-92. Epub 2016 Feb 1. link to original article PubMed
  7. Retrospective: Stamatoullas A, Brice P, Bouabdallah R, Mareschal S, Camus V, Rahal I, Franchi P, Lanic H, Tilly H. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol. 2015 Jul;170(2):179-84. Epub 2015 Apr 19. link to original article PubMed
  8. UK NCRI RAPID: Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. link to original article contains dosing details in abstract PubMed NCT00943423
  9. CALGB 50604: Straus DJ, Jung SH, Pitcher B, Kostakoglu L, Grecula JC, Hsi ED, Schöder H, Popplewell LL, Chang JE, Moskowitz CH, Wagner-Johnston N, Leonard JP, Friedberg JW, Kahl BS, Cheson BD, Bartlett NL. CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood. 2018 Sep 6;132(10):1013-1021. Epub 2018 Jul 26. link to original article contains dosing details in abstract link to PMC article PubMed NCT01132807
  10. GHSG HD16: Fuchs M, Goergen H, Kobe C, Kuhnert G, Lohri A, Greil R, Sasse S, Topp MS, Schäfer E, Hertenstein B, Soekler M, Vogelhuber M, Zijlstra JM, Keller UB, Krause SW, Wilhelm M, Maschmeyer G, Thiemer J, Dührsen U, Meissner J, Viardot A, Eich H, Baues C, Diehl V, Rosenwald A, von Tresckow B, Dietlein M, Borchmann P, Engert A. Positron Emission Tomography-Guided Treatment in Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase III HD16 Trial by the German Hodgkin Study Group. J Clin Oncol. 2019 Nov 1;37(31):2835-2845. Epub 2019 Sep 10. link to original article PubMed NCT00736320

AVD

AVD: Adriamycin (Doxorubicin), Vinblastine, Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Behringer et al. 2014 (GHSG HD13) 2003-2009 Phase 3 (E-de-esc) 1. ABV Not reported
2. ABVD Might have inferior FFTF (primary endpoint)
3. AV Not reported

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • IFRT x 3000 cGy consolidation

References

  1. Behringer K, Goergen H, Hitz F, Zijlstra JM, Greil R, Markova J, Sasse S, Fuchs M, Topp MS, Soekler M, Mathas S, Meissner J, Wilhelm M, Koch P, Lindemann HW, Schalk E, Semrau R, Kriz J, Vieler T, Bentz M, Lange E, Mahlberg R, Hassler A, Vogelhuber M, Hahn D, Mezger J, Krause SW, Skoetz N, Böll B, von Tresckow B, Diehl V, Hallek M, Borchmann P, Stein H, Eich H, Engert A; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015 Apr 11;385(9976):1418-27. Epub 2014 Dec 22. Erratum in: Lancet. 2015 Apr 11;385(9976):1396. link to original article PubMed ISRCTN63474366
    1. Pooled subgroup analysis: Böll B, Goergen H, Behringer K, Bröckelmann PJ, Hitz F, Kerkhoff A, Greil R, von Tresckow B, Eichenauer DA, Bürkle C, Borchmann S, Fuchs M, Diehl V, Engert A, Borchmann P. Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials. Blood. 2016 May 5;127(18):2189-92. Epub 2016 Feb 1. link to original article PubMed

MOPP-ABV

MOPP-ABV: Mustargen (Mechlorethamine), Oncovin (Vincristine), Procarbazine, Prednisone, Adriamycin (Doxorubicin), Bleomycin, Vinblastine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fermé et al. 2007 (EORTC-GELA H8-F) 1993-1999 Phase 3 (E-switch-ooc) See link See link

Chemotherapy

Glucocorticoid therapy

28-day cycle for 3 cycles

Subsequent treatment

  • IFRT consolidation, 3 to 4 weeks later

References

  1. EORTC-GELA H8-F: Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC; GELA. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. link to original article contains dosing details in supplement PubMed NCT00379041

Radiation therapy

RT: Radiation Therapy

Regimen variant #1, 3500 cGy of subtotal nodal irradiation (STNI)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Meyer et al. 2005 (NCIC-CTG/ECOG HD.6 F) 1994-2002 Phase 3 (C) ABVD Seems to have inferior OS1

1Reported efficacy for NCIC-CTG/ECOG HD.6 F is based on the 2011 update.

Radiotherapy

  • STNI 3500 cGy in 20 fractions

4-week course


Regimen variant #2, 3600 cGy of STNI + 400 cGy boost

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fermé et al. 2007 (EORTC-GELA H8-F) 1993-1999 Phase 3 (C) MOPP-ABV, then IFRT Inferior OS

Radiotherapy

  • STNI 3600 cGy in 18 fractions, with 400 cGy boost to involved fields

4-week course


Regimen variant #3, 40 to 4400 cGy of subtotal lymphoid irradiation (STLI)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Horning et al. 1988 NR Phase 3 (C) IFRT, then VBM Might have inferior FFP

Radiotherapy

One course

References

  1. Horning SJ, Hoppe RT, Hancock SL, Rosenberg SA; EORTC Lymphoma Cooperative Group. Vinblastine, bleomycin, and methotrexate: an effective adjuvant in favorable Hodgkin's disease. J Clin Oncol. 1988 Dec;6(12):1822-31. link to original article PubMed
  2. EORTC H6U: Carde P, Hagenbeek A, Hayat M, Monconduit M, Thomas J, Burgers MJ, Noordijk EM, Tanguy A, Meerwaldt JH, Le Fur R, Somers R, Kluin-Nelemans HC, Busson A, Breed WP, Bron D, Holdrinet A, Rutten EH, Michiels JJ, Regnier R, Debusscher L, Musella R, Fargeot P, Thyss A, Cattan A, Rigal-Huguet F, Roth S, Caillou B, Dupouy N, Henry-Amar M; EORTC Lymphoma Cooperative Group. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organisation for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1993 Nov;11(11):2258-72. link to original article PubMed
  3. NCIC-CTG/ECOG HD.6 F: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Bezjak A, Wells WA, Burns BF, Winter JN, Horning SJ, Dar AR, Djurfeldt MS, Ding K, Shepherd LE; National Cancer Institute of Canada Clinical Trials Group; ECOG. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 Jul 20;23(21):4634-42. Epub 2005 Apr 18. link to original article PubMed NCT00002561
    1. Update: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN, Horning SJ, Dar AR, Shustik C, Stewart DA, Crump M, Djurfeldt MS, Chen BE, Shepherd LE; NCIC Clinical Trials Group; ECOG. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med. 2012 Feb 2;366(5):399-408. Epub 2011 Dec 11. link to original article link to PMC article contains dosing details in abstract PubMed
  4. EORTC-GELA H8-F: Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC; GELA. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. link to original article contains dosing details in supplement PubMed NCT00379041

Stanford V

Regimen

Study Dates of enrollment Evidence
Advani et al. 2013 (G4) 1995-2001 Non-randomized

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 40 mg/m2 PO every other day for 6 weeks, then tapered by 10 mg per day over the next 2 weeks

8-week course

Subsequent treatment

  • IFRT consolidation, 1 to 3 weeks later

References

  1. G4: Advani RH, Hoppe RT, Baer D, Mason J, Warnke R, Allen J, Daadi S, Rosenberg SA, Horning SJ. Efficacy of abbreviated Stanford V chemotherapy and involved-field radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial. Ann Oncol. 2013 Apr;24(4):1044-8. Epub 2012 Nov 7. link to original article contains limited protocol link to PMC article PubMed

Untreated, early-stage unfavorable (ESU)

Note: the definition of early stage unfavorable varies across organizations, e.g., EORTC, GHSG, NCIC, and NCCN; see original definitions used in the trials for details.

ABVD

ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Example orders

Regimen variant #1, 2 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Meyer et al. 2005 (NCIC-CTG/ECOG HD.6 U) 1994-2002 Phase 3 (C) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • NCIC-CTG/ECOG HD.6 U: STNI consolidation


Regimen variant #2, 2 cycles with response adaptation

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10 U) 2006-2009 Phase 3 (E-switch-ooc) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • EORTC/LYSA/FIL H10 U, negative interim PET-CT (1 or 2 points on the 5-point Deauville scale): ABVD continuation x 4 (6 total) versus ABVD continuation x 2 (4 total), then INRT consolidation
  • EORTC/LYSA/FIL H10 U, positive interim PET-CT: eBEACOPP salvage, then INRT consolidation


Regimen variant #3, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Meyer et al. 2005 (NCIC-CTG/ECOG HD.6 U) 1994-2002 Phase 3 (E-switch-ooc) ABVD x 2, then STNI Seems to have superior OS1 (primary endpoint)
OS144: 94% vs 87%
(HR 0.50, 95% CI 0.25-0.99)
Eich et al. 2010 (GHSG HD11) 1998-2003 Phase 3 (C) BEACOPP Did not meet primary endpoint of FFTF
von Tresckow et al. 2012 (GHSG HD14) 2003-2008 Phase 3 (C) eBEACOPP-ABVD Inferior FFTF
Fornecker et al. 2022 (BREACH) 2015-03 to 2016-10 Randomized Phase 2 (C) BV-AVD Inferior PET RR after 2 cycles

1Reported efficacy for NCIC-CTG/ECOG HD.6 U is based on the 2011 update.

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

  • GHSG HD11: IFRT x 2000 cGy versus IFRT x 3000 cGy consolidation
  • GHSG HD14 & BREACH: IFRT x 3000 cGy consolidation


Regimen variant #4, 6 to 8 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Carde et al. 1993 (EORTC H6U) 1982-1988 Phase 3 (E-switch-ic) MOPP Superior FFP
Straus et al. 2004 1990-2000 Non-randomized part of phase 3 RCT
Gordon et al. 2012 (ECOG E2496) 1999-2006 Phase 3 (C) Stanford V Did not meet primary endpoint of FFS

Note: EORTC H6U included radiation delivered between cycles 3 & 4. Straus et al. 2004 enrolled patients with stages I, II, and IIIA nonbulky disease and did not distinguish between favorable or unfavorable subtypes. ECOG E2496 gives a range of cycles.

Chemotherapy

28-day cycle for 6 to 8 cycles

Subsequent treatment

References

  1. EORTC H6U: Carde P, Hagenbeek A, Hayat M, Monconduit M, Thomas J, Burgers MJ, Noordijk EM, Tanguy A, Meerwaldt JH, Le Fur R, Somers R, Kluin-Nelemans HC, Busson A, Breed WP, Bron D, Holdrinet A, Rutten EH, Michiels JJ, Regnier R, Debusscher L, Musella R, Fargeot P, Thyss A, Cattan A, Rigal-Huguet F, Roth S, Caillou B, Dupouy N, Henry-Amar M; EORTC Lymphoma Cooperative Group. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organisation for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1993 Nov;11(11):2258-72. link to original article PubMed
  2. Straus DJ, Portlock CS, Qin J, Myers J, Zelenetz AD, Moskowitz C, Noy A, Goy A, Yahalom J. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood. 2004 Dec 1;104(12):3483-9. Epub 2004 Aug 17. link to original article PubMed
  3. NCIC-CTG/ECOG HD.6 U: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Bezjak A, Wells WA, Burns BF, Winter JN, Horning SJ, Dar AR, Djurfeldt MS, Ding K, Shepherd LE; National Cancer Institute of Canada Clinical Trials Group; ECOG. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 Jul 20;23(21):4634-42. Epub 2005 Apr 18. link to original article PubMed NCT00002561
    1. Update: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN, Horning SJ, Dar AR, Shustik C, Stewart DA, Crump M, Djurfeldt MS, Chen BE, Shepherd LE; NCIC Clinical Trials Group; ECOG. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med. 2012 Feb 2;366(5):399-408. Epub 2011 Dec 11. link to original article link to PMC article contains dosing details in abstract PubMed
  4. GHSG HD11: Eich HT, Diehl V, Görgen H, Pabst T, Markova J, Debus J, Ho A, Dörken B, Rank A, Grosu AL, Wiegel T, Karstens JH, Greil R, Willich N, Schmidberger H, Döhner H, Borchmann P, Müller-Hermelink HK, Müller RP, Engert A. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010 Sep 20;28(27):4199-206. Epub 2010 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00264953
    1. Pooled subgroup analysis: Böll B, Görgen H, Fuchs M, Pluetschow A, Eich HT, Bargetzi MJ, Weidmann E, Junghanß C, Greil R, Scherpe A, Schmalz O, Eichenauer DA, von Tresckow B, Rothe A, Diehl V, Engert A, Borchmann P. ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol. 2013 Apr 20;31(12):1522-9. Epub 2013 Mar 18. link to original article PubMed
    2. Pooled update: Sasse S, Bröckelmann PJ, Goergen H, Plütschow A, Müller H, Kreissl S, Buerkle C, Borchmann S, Fuchs M, Borchmann P, Diehl V, Engert A. Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 trials. J Clin Oncol. 2017 Jun 20;35(18):1999-2007. Epub 2017 Apr 18. link to original article PubMed
  5. GHSG HD14: von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. link to original article contains dosing details in manuscript PubMed ISRCTN04761296
  6. ECOG E2496: Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: An Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article link to PMC article PubMed NCT00003389
    1. Subgroup analysis: Evens AM, Hong F, Gordon LI, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Gospodarowicz M, Cheson BD, Stiff PJ, Advani R, Miller TP, Hoppe RT, Kahl BS, Horning SJ. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013 Apr;161(1):76-86. Epub 2013 Jan 29. link to original article link to PMC article PubMed
    2. Subgroup analysis: Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin lymphoma: a subset analysis of the North American Intergroup E2496 trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol link to PMC article PubMed
  7. EORTC/LYSA/FIL H10: Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains dosing details in abstract PubMed NCT00433433
    1. Update: André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. link to original article PubMed
    2. Update: Federico M, Fortpied C, Stepanishyna Y, Gotti M, van der Maazen R, Cristinelli C, Re A, Plattel W, Lazarovici J, Merli F, Specht L, Schiano de Colella JM, Hutchings M, Versari A, Edeline V, Stamatoulas A, Girinsky T, Ricardi U, Aleman B, Meulemans B, Tonino S, Raemaekers J, André M. Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma. J Clin Oncol. 2024 Jan 1;42(1):19-25. Epub 2023 Nov 15. link to original article link to PMC article PubMed
  8. Retrospective: Stamatoullas A, Brice P, Bouabdallah R, Mareschal S, Camus V, Rahal I, Franchi P, Lanic H, Tilly H. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol. 2015 Jul;170(2):179-84. Epub 2015 Apr 19. link to original article PubMed
  9. BREACH: Fornecker LM, Lazarovici J, Aurer I, Casasnovas RO, Gac AC, Bonnet C, Bouabdallah K, Feugier P, Specht L, Molina L, Touati M, Borel C, Stamatoullas A, Nicolas-Virelizier E, Pascal L, Lugtenburg P, Di Renzo N, Vander Borght T, Traverse-Glehen A, Dartigues P, Hutchings M, Versari A, Meignan M, Federico M, André M; LYSA-FIL-EORTC Intergroup. Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial. J Clin Oncol. 2023 Jan 10;41(2):327-335. Epub 2022 Jul 22. link to original article contains dosing details in manuscript PubMed NCT02292979

A-AVD

A-AVD: Adcetris (Brentuximab vedotin), Adriamycin (Doxorubicin), Vinblastine, Dacarbazine
A+AVD: Adcetris (Brentuximab vedotin), Adriamycin (Doxorubicin), Vinblastine, Dacarbazine
BV + AVD: Brentuximab Vedotin, Adriamycin (Doxorubicin), Vinblastine, Dacarbazine

Regimen variant #1, uncapped BV

Study Dates of enrollment Evidence
Kumar et al. 2016 (MSK 13-034) 2013-06 to 2015-02 Phase 2

Antibody-drug conjugate therapy

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

  • MSK 13-034, patients with a negative repeat PET-CT: ISRT consolidation


Regimen variant #2, capped BV

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fornecker et al. 2022 (BREACH) 2015-03 to 2016-10 Randomized Phase 2 (E-switch-ooc) ABVD x 4 Superior PET RR after 2 cycles (primary endpoint)

Antibody-drug conjugate therapy

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

  • IFRT x 3000 cGy consolidation

References

  1. MSK 13-034: Kumar A, Casulo C, Yahalom J, Schöder H, Barr PM, Caron P, Chiu A, Constine LS, Drullinsky P, Friedberg JW, Gerecitano JF, Hamilton A, Hamlin PA, Horwitz SM, Jacob AG, Matasar MJ, McArthur GN, McCall SJ, Moskowitz AJ, Noy A, Palomba ML, Portlock CS, Straus DJ, VanderEls N, Verwys SL, Yang J, Younes A, Zelenetz AD, Zhang Z, Moskowitz CH. Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2016 Sep 15;128(11):1458-64. Epub 2016 Jul 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01868451
  2. BREACH: Fornecker LM, Lazarovici J, Aurer I, Casasnovas RO, Gac AC, Bonnet C, Bouabdallah K, Feugier P, Specht L, Molina L, Touati M, Borel C, Stamatoullas A, Nicolas-Virelizier E, Pascal L, Lugtenburg P, Di Renzo N, Vander Borght T, Traverse-Glehen A, Dartigues P, Hutchings M, Versari A, Meignan M, Federico M, André M; LYSA-FIL-EORTC Intergroup. Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial. J Clin Oncol. 2023 Jan 10;41(2):327-335. Epub 2022 Jul 22. link to original article contains dosing details in manuscript PubMed NCT02292979

BEACOPP

BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
BEACOPPbaseline

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eich et al. 2010 (GHSG HD11) 1998-2003 Phase 3 (E-esc) ABVD Did not meet primary endpoint of FFTF

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 4 cycles

Subsequent treatment

  • IFRT x 2000 cGy versus IFRT x 3000 cGy consolidation

References

  1. GHSG HD11: Eich HT, Diehl V, Görgen H, Pabst T, Markova J, Debus J, Ho A, Dörken B, Rank A, Grosu AL, Wiegel T, Karstens JH, Greil R, Willich N, Schmidberger H, Döhner H, Borchmann P, Müller-Hermelink HK, Müller RP, Engert A. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010 Sep 20;28(27)99-206. Epub 2010 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00264953
    1. Pooled subgroup analysis: Böll B, Görgen H, Fuchs M, Pluetschow A, Eich HT, Bargetzi MJ, Weidmann E, Junghanß C, Greil R, Scherpe A, Schmalz O, Eichenauer DA, von Tresckow B, Rothe A, Diehl V, Engert A, Borchmann P. ABVD in older patients with early-stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD10 and HD11 trials. J Clin Oncol. 2013 Apr 20;31(12):1522-9. Epub 2013 Mar 18. link to original article PubMed
    2. Pooled update: Sasse S, Bröckelmann PJ, Goergen H, Plütschow A, Müller H, Kreissl S, Buerkle C, Borchmann S, Fuchs M, Borchmann P, Diehl V, Engert A. Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 trials. J Clin Oncol. 2017 Jun 20;35(18):1999-2007. Epub 2017 Apr 18. link to original article PubMed

eBEACOPP-ABVD

eBEACOPP-ABVD: escalated Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone, followed by Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Tresckow et al. 2012 (GHSG HD14) 2003-2008 Phase 3 (E-esc) ABVD x 4 Superior FFTF (primary endpoint)
FFTF60: 94.8% vs 87.7%
(HR 0.44, 95% CI 0.30-0.66)
Borchmann et al. 2021 (GHSG HD17) 2012-2017 Non-randomized part of phase 3 RCT

Chemotherapy, eBEACOPP portion (cycles 1 & 2)

Glucocorticoid therapy, eBEACOPP portion (cycles 1 & 2)

Supportive therapy, eBEACOPP portion (cycles 1 & 2)

  • Filgrastim (Neupogen) (dose not specified) SC once per day, starting on day 8, continues until ANC greater than 1000/μL for 3 consecutive days

Chemotherapy, ABVD portion (cycles 3 & 4)

21-day cycle for 2 cycles, then 28-day cycle for 2 cycles (eBEACOPP x 2; ABVD x 2)

Subsequent treatment

  • GHSG HD14: IFRT x 3000 cGy consolidation
  • GHSG HD17, PET4 positive: IFRT x 3000 cGy consolidation
  • GHSG HD17, PET4 negative: IFRT x 3000 cGy consolidation versus no further treatment

References

  1. GHSG HD14: von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. link to original article contains dosing details in manuscript PubMed ISRCTN04761296
  2. GHSG HD17: Borchmann P, Plütschow A, Kobe C, Greil R, Meissner J, Topp MS, Ostermann H, Dierlamm J, Mohm J, Thiemer J, Sökler M, Kerkhoff A, Ahlborn M, Halbsguth TV, Martin S, Keller U, Balabanov S, Pabst T, Vogelhuber M, Hüttmann A, Wilhelm M, Zijlstra JM, Moccia A, Kuhnert G, Bröckelmann PJ, von Tresckow B, Fuchs M, Klimm B, Rosenwald A, Eich H, Baues C, Marnitz S, Hallek M, Diehl V, Dietlein M, Engert A. PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):223-234. link to original article PubMed NCT01356680

EBVP

EBVP: Epirubicin, Bleomycin, Vinblastine, Prednisone

Regimen

Study Dates of enrollment Evidence
Thomas et al. 2017 (EORTC-GELA H9-F) 1998-2004 Non-randomized part of phase 3 RCT

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. EORTC-GELA H9-F: Thomas J, Fermé C, Noordijk EM, Morschhauser F, Girinsky T, Gaillard I, Lugtenburg PJ, André M, Lybeert MLM, Stamatoullas A, Beijert M, Hélias P, Eghbali H, Gabarre J, van der Maazen RWM, Jaubert J, Bouabdallah K, Boulat O, Roesink JM, Christian B, Ong F, Bordessoule D, Tertian G, Gonzalez H, Vranovsky A, Quittet P, Tirelli U, de Jong D, Audouin J, Aleman BMP, Henry-Amar M; EORTC; GELA. Comparison of 3600 cGy, 2000 cGy, or no radiation therapy after 6 cycles of EBVP chemotherapy and complete remission in early-stage Hodgkin lymphoma without risk factors: results of the EORTC-GELA H9-F intergroup randomized trial. Int J Radiat Oncol Biol Phys. 2018 Apr 1;100(5):1133-1145. Epub 2017 Oct 27. link to original article contains dosing details in manuscript PubMed NCT00005584

MOPP-ABV

MOPP-ABV: Mustargen (Mechlorethamine), Oncovin (Vincristine), Procarbazine, Prednisone, Adriamycin (Doxorubicin), Bleomycin, Vinblastine

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fermé et al. 2007 (EORTC-GELA H8-U) 1993-1999 Phase 3 (E-de-esc) See link See link

Chemotherapy

Glucocorticoid therapy

28-day cycle for 4 cycles

Subsequent treatment

  • IFRT versus STNI consolidation, in 3 to 4 weeks


Regimen variant #2, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Noordijk et al. 2006 (EORTC H7-U) 1988-1993 Phase 3 (C) EBVP Seems to have superior OS
Fermé et al. 2007 (EORTC-GELA H8-U) 1993-1999 Phase 3 (C) See link See link

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 cycles

Subsequent treatment

  • IFRT consolidation, in 3 to 4 weeks

References

  1. EORTC H7-U: Noordijk EM, Carde P, Dupouy N, Hagenbeek A, Krol AD, Kluin-Nelemans JC, Tirelli U, Monconduit M, Thomas J, Eghbali H, Aleman BM, Bosq J, Vovk M, Verschueren TA, Pény AM, Girinsky T, Raemaekers JM, Henry-Amar M. Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol. 2006 Jul 1;24(19):3128-35. Epub 2006 Jun 5. link to original article PubMed
  2. EORTC-GELA H8-U: Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC; GELA. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. link to original article contains dosing details in supplement PubMed NCT00379041

RABVD

RABVD: Rituximab, Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Dates of enrollment Evidence
Kasamon et al. 2012 (J0615) 2006-NR Phase 2, fewer than 20 pts in subgroup

Note: Patients were NOT required to have CD20+ disease.

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Pre-phase: 375 mg/m2 IV once one week prior to cycle 1 of ABVD
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2, 4, 6: 375 mg/m2 IV once on day 1

Chemotherapy

28-day cycle for 6 to 8 cycles

References

  1. J0615: Kasamon YL, Jacene HA, Gocke CD, Swinnen LJ, Gladstone DE, Perkins B, Link BK, Popplewell LL, Habermann TM, Herman JM, Matsui WH, Jones RJ, Ambinder RF. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012 May 3;119(18):4129-32. Epub 2012 Feb 16. link to original article contains partial protocol link to PMC article PubMed NCT00369681

Stanford V

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gordon et al. 2012 (ECOG E2496) 1999-2006 Phase 3 (E-esc) ABVD Did not meet primary endpoint of FFS

Note: In the Advani et al. 2015 subgroup analysis, the Stanford V regimen is described as "once per week for 12 weeks." However, the regimen has previously been described as being 4-week cycles for 3 cycles (same duration, but schedule is different). Until this discrepancy is resolved, we replicate the 4-week cycle version here:

Chemotherapy

Glucocorticoid therapy

28-day cycle for 3 cycles

Subsequent treatment

  • IFRT x 3600 cGy consolidation

References

  1. ECOG E2496: Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: An Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article link to PMC article PubMed NCT00003389
    1. Subgroup analysis: Evens AM, Hong F, Gordon LI, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Gospodarowicz M, Cheson BD, Stiff PJ, Advani R, Miller TP, Hoppe RT, Kahl BS, Horning SJ. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013 Apr;161(1):76-86. Epub 2013 Jan 29. link to original article link to PMC article PubMed
    2. Subgroup analysis: Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin lymphoma: a subset analysis of the North American Intergroup E2496 trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol link to PMC article PubMed

Untreated, advanced stage

Note: the definition of advanced stage varies across organizations, e.g., EORTC, GHSG, NCIC, and NCCN; see original definitions used in the trials for details.

ABVD

ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Example orders

Regimen variant #1, 2 cycles with response adaptation

Study Dates of enrollment Evidence
Johnson et al. 2016 (RATHL) 2008-2012 Non-randomized part of phase 3 RCT
Zinzani et al. 2016 (HD0801) 2008-2013 Non-randomized
Gallamini et al. 2018 (GITIL/FIL HD 0607) 2008-2014 Non-randomized part of phase 3 RCT
Press et al. 2016 (SWOG S0816) 2009-2012 Phase 2

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

  • HD0801, negative PET-CT by Juweid's criteria: ABVD continuation x 4 (6 total)
  • HD0801, positive PET-CT by Juweid's criteria: IGEV salvage
  • SWOG S0816 & GITIL/FIL HD 0607, negative PET-CT by Deauville score (1 to 3): ABVD continuation x 4 (6 total)
  • SWOG S0816, positive PET-CT by Deauville score (4 or 5): eBEACOPP salvage
  • RATHL, negative PET-CT by Deauville score (1 to 3): ABVD continuation x 4 (6 total) versus AVD de-intensification x 4
  • RATHL, positive PET-CT by Deauville score (4 or 5): eBEACOPP or BEACOPP-14 salvage, specified in advance
  • GITIL/FIL HD 0607, positive PET-CT by Deauville score (4 or 5): eBEACOPP versus R-BEACOPP salvage


Regimen variant #2, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gobbi et al. 2005 (GITIL HD9601) 1996-2000 Phase 3 (C) 1. MOPPEBVCAD Did not meet primary endpoint of FFS
2. Modified Stanford V Superior FFS
Federico et al. 2009 (GITIL/FIL HD2000) 2000-2007 Phase 3 (C) 1. eBEACOPP x 4, then BEACOPP x 2 Did not meet primary endpoint of FFS1
2. COPPEBVCAD Did not meet primary endpoint of FFS
Johnson et al. 2016 (RATHL) 2008-2012 Non-randomized part of phase 3 RCT
Zinzani et al. 2016 (HD0801) 2008-2013 Non-randomized
Gallamini et al. 2018 (GITIL/FIL HD 0607) 2008-2014 Non-randomized part of phase 3 RCT
Press et al. 2016 (SWOG S0816) 2009-2012 Phase 2
Connors et al. 2017 (ECHELON-1) 2012-2016 Phase 3 (C) A-AVD Inferior OS2

1Reported efficacy for GITIL/FIL HD2000 is based on the 2015 update.
2Reported efficacy for ECHELON-1 is based on the 2022 update.
Note: Zinzani et al. 2016 does not describe the details of radiotherapy. Note that ECHELON-1 specifies "up to" 6 cycles of therapy, but does not explain circumstance in which fewer than 6 would be given.

Preceding treatment

  • HD0801: ABVD induction x 2, with negative PET-CT by Juweid's criteria
  • SWOG S0816, RATHL, GITIL/FIL HD 0607: ABVD induction x 2, with negative PET-CT by Deauville score (1 to 3)

Chemotherapy

28-day cycle for 6 cycles (see note)

Subsequent treatment


Regimen variant #3, 8 cycles (ABVD8)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 1975 1973-04 to 1974-01 Phase 3 (E-switch-ic) MOPP Did not meet efficacy endpoints
Santoro et al. 1987 1974-1982 Phase 3 (E-switch-ic) MOPP Seems to have superior OS
Canellos et al. 1992 (CALGB 8251) 1982-NR Phase 3 (E-switch-ic) 1. MOPP Seems to have superior EFS1
2. MOPP/ABVD Did not meet endpoint of OS1
Duggan et al. 2003 (CALGB-8952) NR-1995 Phase 3 (C) MOPP-ABV Did not meet primary endpoint of CR rate
Johnson et al. 2005 (UKLG LY09) 1998-2001 Phase 3 (C) 1. ChlVPP/EVA
2. ChlVPP/PABlOE 		Did not meet primary endpoint of EFS
Hoskin et al. 2009 (BNLI STANFORDV) 1998-2006 Phase 3 (C) Stanford V Did not meet primary endpoint of PFS
Gordon et al. 2012 (ECOG E2496) 1999-2006 Phase 3 (C) Stanford V Did not meet primary endpoint of FFS
Viviani et al. 2011 (GSM-HD) 2000-2007 Phase 3 (C) BEACOPP4+4 Seems to have inferior FFFP
Carde et al. 2016 (EORTC 20012) 2002-2010 Phase 3 (C) BEACOPP4+4 Did not meet primary endpoint of EFS
Mounier et al. 2014 (LYSA H34) 2003-2008 Phase 3 (C) BEACOPP4+4 Might have inferior EFS

1Reported efficacy for CALGB 8251 is based on the 2009 update.
Note: Duggan et al. 2003 specified that chemotherapy was given until CR plus an additional two cycles, for a minimum of eight cycles and a maximum of 10 cycles.

Chemotherapy

28-day cycle for 8 cycles

References

  1. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975 Jul;36(1):252-9. link to original article PubMed
  2. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F, Tesoro-Tess JD, Banfi A. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987 Jan;5(1):27-37. link to original article PubMed
  3. CALGB 8251: Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. link to original article PubMed
    1. Update: Canellos GP, Niedzwiecki D. Long-term follow-up of Hodgkin's disease trial. N Engl J Med. 2002 May 2;346(18):1417-8. link to original article PubMed
    2. Update: Canellos GP, Niedzwiecki D, Johnson JL. Long-term follow-up of survival in Hodgkin's lymphoma. N Engl J Med. 2009 Dec 10;361(24):2390-1. link to original article PubMed
  4. CALGB-8952: Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, Canellos GP, Peterson BA. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol. 2003 Feb 15;21(4):607-14. link to original article does not contain dosing details PubMed
  5. GITIL HD9601: Gobbi PG, Levis A, Chisesi T, Broglia C, Vitolo U, Stelitano C, Pavone V, Cavanna L, Santini G, Merli F, Liberati M, Baldini L, Deliliers GL, Angelucci E, Bordonaro R, Federico M; Intergruppo Italiano Linfomi. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol. 2005 Dec 20;23(36):9198-207. Epub 2005 Sep 19. link to original article contains dosing details in abstract PubMed
    1. Update: Chisesi T, Bellei M, Luminari S, Montanini A, Marcheselli L, Levis A, Gobbi P, Vitolo U, Stelitano C, Pavone V, Merli F, Liberati M, Baldini L, Bordonaro R, Pesce EA, Federico M. Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol. 2011 Nov 10;29(32):4227-33. Epub 2011 Oct 11. link to original article PubMed
  6. UKLG LY09: Johnson PW, Radford JA, Cullen MH, Sydes MR, Walewski J, Jack AS, MacLennan KA, Stenning SP, Clawson S, Smith P, Ryder D, Hancock BW; United Kingdom Lymphoma Group. Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519). J Clin Oncol. 2005 Dec 20;23(36):9208-18. Epub 2005 Nov 28. link to original article contains dosing details in manuscript PubMed NCT00003421
    1. Subgroup analysis: Johnson PW, Sydes MR, Hancock BW, Cullen M, Radford JA, Stenning SP. Consolidation radiotherapy in patients with advanced Hodgkin's lymphoma: survival data from the UKLG LY09 randomized controlled trial (ISRCTN97144519). J Clin Oncol. 2010 Jul 10;28(20):3352-9. Epub 2010 May 24. link to original article PubMed
  7. GITIL/FIL HD2000: Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, Montanini A, La Sala A, Merli F, Stelitano C, Pozzi S, Scalone R, Di Renzo N, Musto P, Baldini L, Cervetti G, Angrilli F, Mazza P, Brugiatelli M, Gobbi PG; Gruppo Italiano per lo Studio dei Linfomi. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009 Feb 10;27(5):805-11. Epub 2009 Jan 5. link to original article contains dosing details in abstract PubMed NCT00443677
    1. Update: Merli F, Luminari S, Gobbi PG, Cascavilla N, Mammi C, Ilariucci F, Stelitano C, Musso M, Baldini L, Galimberti S, Angrilli F, Polimeno G, Scalzulli PR, Ferrari A, Marcheselli L, Federico M. Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced Hodgkin lymphoma: a study by Fondazione Italiana Linfomi. J Clin Oncol. 2016 Apr 10;34(11):1175-81. Epub 2015 Dec 28. link to original article PubMed
  8. BNLI STANFORDV: Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW, Smith P, Qian W, Patrick P, Popova B, Pettitt A, Cunningham D, Pettengell R, Sweetenham J, Linch D, Johnson PW. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009 Nov 10;27(32):5390-6. Epub 2009 Sep 8. link to original article PubMed NCT00041210
  9. GSM-HD: Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM, Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM, Pregno P, Gotti M, Gallamini A, Rota Scalabrini D, Bonadonna G, Gianni AM; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203-12. link to original article contains dosing details in manuscript PubMed NCT01251107
  10. ECOG E2496: Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: An Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article link to PMC article PubMed NCT00003389
    1. Subgroup analysis: Evens AM, Hong F, Gordon LI, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Gospodarowicz M, Cheson BD, Stiff PJ, Advani R, Miller TP, Hoppe RT, Kahl BS, Horning SJ. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013 Apr;161(1):76-86. Epub 2013 Jan 29. link to original article link to PMC article PubMed
    2. Subgroup analysis: Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin lymphoma: a subset analysis of the North American Intergroup E2496 trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol link to PMC article PubMed
  11. LYSA H34: Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M, Gabarre J, Casasnovas O, Jaubert J, Colin P, Delmer A, Devidas A, Bachy E, Nicolas-Virelizier E, Aoudjhane A, Humbrecht C, Andre M, Carde P; Lymphoma Study Association. ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014 Aug;25(8):1622-8. Epub 2014 May 14. link to original article contains dosing details in manuscript PubMed RECF0219
  12. Retrospective: Stamatoullas A, Brice P, Bouabdallah R, Mareschal S, Camus V, Rahal I, Franchi P, Lanic H, Tilly H. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol. 2015 Jul;170(2):179-84. Epub 2015 Apr 19. link to original article PubMed
  13. HD0801: Zinzani PL, Broccoli A, Gioia DM, Castagnoli A, Ciccone G, Evangelista A, Santoro A, Ricardi U, Bonfichi M, Brusamolino E, Rossi G, Anastasia A, Zaja F, Vitolo U, Pavone V, Pulsoni A, Rigacci L, Gaidano G, Stelitano C, Salvi F, Rusconi C, Tani M, Freilone R, Pregno P, Borsatti E, Sacchetti GM, Argnani L, Levis A. Interim positron emission tomography response-adapted therapy in advanced-stage Hodgkin lymphoma: final results of the phase II part of the HD0801 study. J Clin Oncol. 2016 Apr 20;34(12):1376-85. Epub 2016 Feb 16. link to original article contains dosing details in manuscript PubMed NCT00784537
  14. SWOG S0816: Press OW, Li H, Schöder H, Straus DJ, Moskowitz CH, LeBlanc M, Rimsza LM, Bartlett NL, Evens AM, Mittra ES, LaCasce AS, Sweetenham JW, Barr PM, Fanale MA, Knopp MV, Noy A, Hsi ED, Cook JR, Lechowicz MJ, Gascoyne RD, Leonard JP, Kahl BS, Cheson BD, Fisher RI, Friedberg JW. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016 Jun 10;34(17):2020-7. Epub 2016 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00822120
    1. Update: Stephens DM, Li H, Schöder H, Straus DJ, Moskowitz CH, LeBlanc M, Rimsza LM, Bartlett NL, Evens AM, LaCasce AS, Barr PM, Knopp MV, Hsi ED, Leonard JP, Kahl BS, Smith SM, Friedberg JW. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma. Blood. 2019 Oct 10;134(15):1238-1246. link to original article link to PMC article PubMed
  15. EORTC 20012: Carde P, Karrasch M, Fortpied C, Brice P, Khaled H, Casasnovas O, Caillot D, Gaillard I, Bologna S, Ferme C, Lugtenburg PJ, Morschhauser F, Aurer I, Coiffier B, Meyer R, Seftel M, Wolf M, Glimelius B, Sureda A, Mounier N. Eight cycles of ABVD versus four cycles of BEACOPPescalated plus four cycles of BEACOPPbaseline in stage III to IV, International Prognostic Score ≥ 3, high-risk Hodgkin lymphoma: First results of the phase III EORTC 20012 Intergroup trial. J Clin Oncol. 2016 Jun 10;34(17):2028-36. Epub 2016 Apr 25. link to original article contains dosing details in manuscript PubMed NCT00049595
  16. RATHL: Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, d'Amore F, Enblad G, Franceschetto A, Fulham M, Luminari S, O'Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016 Jun 23;374(25):2419-29. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00678327
    1. Update: Luminari S, Fossa A, Trotman J, Molin D, d'Amore F, Enblad G, Berkahn L, Barrington SF, Radford J, Federico M, Kirkwood AA, Johnson PWM. Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial. J Clin Oncol. 2024 Jan 1;42(1):13-18. Epub 2023 Oct 26. link to original article link to PMC article PubMed
  17. ECHELON-1: Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med. 2018 Jan 25;378(4):331-344. Epub 2017 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01712490
    1. Subgroup analysis: Ramchandren R, Advani RH, Ansell SM, Bartlett NL, Chen R, Connors JM, Feldman T, Forero-Torres A, Friedberg JW, Gopal AK, Gordon LI, Kuruvilla J, Savage KJ, Younes A, Engley G, Manley TJ, Fenton K, Straus DJ. Brentuximab vedotin plus chemotherapy in North American subjects with newly diagnosed stage III or IV Hodgkin lymphoma. Clin Cancer Res. 2019 Mar 15;25(6):1718-1726. Epub 2019 Jan 7. link to original article PubMed
    2. Update: Straus DJ, Długosz-Danecka M, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Ramchandren R, Zinzani PL, Hutchings M, Connors JM, Radford J, Munoz J, Kim WS, Advani R, Ansell SM, Younes A, Miao H, Liu R, Fenton K, Forero-Torres A, Gallamini A. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2020 Mar 5;135(10):735-742. link to original article PubMed
    3. Update: Straus DJ, Długosz-Danecka M, Connors JM, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Ramchandren R, Zinzani PL, Hutchings M, Munoz J, Lee HJ, Kim WS, Advani R, Ansell SM, Younes A, Gallamini A, Liu R, Little M, Fenton K, Fanale M, Radford J. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8(6):e410-e421. link to original article PubMed
    4. Update: Ansell SM, Radford J, Connors JM, Długosz-Danecka M, Kim WS, Gallamini A, Ramchandren R, Friedberg JW, Advani R, Hutchings M, Evens AM, Smolewski P, Savage KJ, Bartlett NL, Eom HS, Abramson JS, Dong C, Campana F, Fenton K, Puhlmann M, Straus DJ; ECHELON-1 Study Group. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. N Engl J Med. 2022 Jul 28;387(4):310-320. Epub 2022 Jul 13. link to original article PubMed
  18. GITIL/FIL HD 0607: Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mulé A, Picardi M, Romano A, Cantonetti M, La Nasa G, Trentin L, Bolis S, Rapezzi D, Battistini R, Gottardi D, Gavarotti P, Corradini P, Cimminiello M, Schiavotto C, Parvis G, Zanotti R, Gini G, Ferreri AJM, Viero P, Miglino M, Billio A, Avigdor A, Biggi A, Fallanca F, Ficola U, Gregianin M, Chiaravalloti A, Prosperini G, Bergesio F, Chauvie S, Pavoni C, Gianni AM, Rambaldi A. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018 Feb 10;36(5):454-462. Epub 2018 Jan 23. link to original article contains dosing details in abstract PubMed NCT00795613
    1. Update: Gallamini A, Rossi A, Patti C, Picardi M, Romano A, Cantonetti M, Oppi S, Viviani S, Bolis S, Trentin L, Gini G, Battistini R, Chauvie S, Sorasio R, Pavoni C, Zanotti R, Cimminiello M, Schiavotto C, Viero P, Mulé A, Fallanca F, Ficola U, Tarella C, Guerra L, Rambaldi A. Consolidation Radiotherapy Could Be Safely Omitted in Advanced Hodgkin Lymphoma With Large Nodal Mass in Complete Metabolic Response After ABVD: Final Analysis of the Randomized GITIL/FIL HD0607 Trial. J Clin Oncol. 2020 Nov 20;38(33):3905-3913. Epub 2020 Sep 18. Erratum in: J Clin Oncol. 2021 Jan 1;39(1):96. link to original article PubMed

ABVD, DD-DI

ABVD, DD-DI: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine, Dose-Dense and Dose-Intense

Regimen

Study Evidence
Russo et al. 2014 Phase 2

Chemotherapy

Supportive therapy

21-day cycle for 6 cycles

References

  1. Russo F, Corazzelli G, Frigeri F, Capobianco G, Aloj L, Volzone F, De Chiara A, Bonelli A, Gatani T, Marcacci G, Donnarumma D, Becchimanzi C, de Lutio E, Ionna F, De Filippi R, Lastoria S, Pinto A. A phase II study of dose-dense and dose-intense ABVD (ABVD(DD-DI) ) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma. Br J Haematol. 2014 Jul;166(1):118-29. Epub 2014 Mar 27. link to original article contains dosing details in manuscript PubMed

AVD

AVD: Adriamycin (Doxorubicin), Vinblastine, Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Johnson et al. 2016 (RATHL) 2008-2012 Phase 3 (E-de-esc) ABVD Non-inferior PFS361 (primary endpoint)

1Reported efficacy is based on the 2023 update.

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

References

  1. RATHL: Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, d'Amore F, Enblad G, Franceschetto A, Fulham M, Luminari S, O'Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016 Jun 23;374(25):2419-29. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00678327
    1. Update: Luminari S, Fossa A, Trotman J, Molin D, d'Amore F, Enblad G, Berkahn L, Barrington SF, Radford J, Federico M, Kirkwood AA, Johnson PWM. Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial. J Clin Oncol. 2024 Jan 1;42(1):13-18. Epub 2023 Oct 26. link to original article link to PMC article PubMed

A-AVD

A-AVD: Adcetris (Brentuximab vedotin), Adriamycin (Doxorubicin), Vinblastine, Dacarbazine
A+AVD: Adcetris (Brentuximab vedotin), Adriamycin (Doxorubicin), Vinblastine, Dacarbazine
B-AVD: Brentuximab vedotin, Adriamycin (Doxorubicin), Vinblastine, Dacarbazine
AVD-A: Adriamycin (Doxorubicin), Vinblastine, Dacarbazine, Adcetris (Brentuximab vedotin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Younes et al. 2013 (SGN35-009) 2010-2012 Phase 1
Connors et al. 2017 (ECHELON-1) 2012-2016 Phase 3 (E-RT-switch-ooc) ABVD Seems to have superior mPFS (primary endpoint)
mPFS24: 82.1% vs 77.2%
(HR 0.77, 95% CI 0.60-0.98)

Superior OS1 (secondary endpoint)
OS72: 93.9% vs 89.4%
(HR 0.59, 95% CI 0.40-0.88)

1Reported efficacy for ECHELON-1 is based on the 2022 update.
Note: SGN35-009 was a phase I trial but had greater than 20 patients in the MTD expansion cohort.

Antibody-drug conjugate therapy

Chemotherapy

28-day cycle for up to 6 cycles

Subsequent treatment

  • SGN35-009: Consolidation radiotherapy was permitted at the investigator's discretion

References

  1. SGN35-009: Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, Huebner D, Ansell SM. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013 Dec;14(13):1348-56. Epub 2013 Nov 15. link to original article contains dosing details in manuscript PubMed NCT01060904
    1. Update: Connors JM, Ansell SM, Fanale M, Park SI, Younes A. Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma. Blood. 2017 Sep 14;130(11):1375-1377. Epub 2017 Jul 21. link to original article link to PMC article PubMed
  2. ECHELON-1: Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med. 2018 Jan 25;378(4):331-344. Epub 2017 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01712490
    1. Subgroup analysis: Ramchandren R, Advani RH, Ansell SM, Bartlett NL, Chen R, Connors JM, Feldman T, Forero-Torres A, Friedberg JW, Gopal AK, Gordon LI, Kuruvilla J, Savage KJ, Younes A, Engley G, Manley TJ, Fenton K, Straus DJ. Brentuximab vedotin plus chemotherapy in North American subjects with newly diagnosed stage III or IV Hodgkin lymphoma. Clin Cancer Res. 2019 Mar 15;25(6):1718-1726. Epub 2019 Jan 7. link to original article PubMed
    2. Update: Straus DJ, Długosz-Danecka M, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Ramchandren R, Zinzani PL, Hutchings M, Connors JM, Radford J, Munoz J, Kim WS, Advani R, Ansell SM, Younes A, Miao H, Liu R, Fenton K, Forero-Torres A, Gallamini A. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2020 Mar 5;135(10):735-742. link to original article PubMed
    3. Update: Straus DJ, Długosz-Danecka M, Connors JM, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Ramchandren R, Zinzani PL, Hutchings M, Munoz J, Lee HJ, Kim WS, Advani R, Ansell SM, Younes A, Gallamini A, Liu R, Little M, Fenton K, Fanale M, Radford J. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8(6):e410-e421. link to original article PubMed
    4. Update: Ansell SM, Radford J, Connors JM, Długosz-Danecka M, Kim WS, Gallamini A, Ramchandren R, Friedberg JW, Advani R, Hutchings M, Evens AM, Smolewski P, Savage KJ, Bartlett NL, Eom HS, Abramson JS, Dong C, Campana F, Fenton K, Puhlmann M, Straus DJ; ECHELON-1 Study Group. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. N Engl J Med. 2022 Jul 28;387(4):310-320. Epub 2022 Jul 13. link to original article PubMed
  3. SWOG S1826: NCT03907488

BEACOPP

BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
bBEACOPP: baseline Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Diehl et al. 1997 1991-1993 Non-randomized ORR: 93%
Diehl et al. 1998 (GHSG HD9) 1993-1998 Phase 3 (E-switch-ic) 1. Escalated dose BEACOPP Inferior FFTF
2. COPP/ABVD Seems to have superior OS

Note: this is technically "BEACOPP II." The original "BEACOPP I" is detailed in Diehl et al. 1997 but is of historical interest, only.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 8 cycles

References

  1. Diehl V, Sieber M, Rüffer U, Lathan B, Hasenclever D, Pfreundschuh M, Loeffler M, Lieberz D, Koch P, Adler M, Tesch H; German Hodgkin's Lymphoma Study Group. BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin's disease. Ann Oncol. 1997 Feb;8(2):143-8. link to original article contains dosing details in manuscript PubMed
  2. GHSG HD9: Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rueffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Duehmke E, Georgii A, Loeffler M. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 1998 Dec;16(12):3810-21. link to original articlecontains dosing details in manuscript PubMed
    1. Update: Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. Erratum in: N Engl J Med. 2005 Aug 18;353(7):744. link to original article contains dosing details in abstract PubMed
    2. Update: Engert A, Diehl V, Franklin J, Lohri A, Dörken B, Ludwig WD, Koch P, Hänel M, Pfreundschuh M, Wilhelm M, Trümper L, Aulitzky WE, Bentz M, Rummel M, Sezer O, Müller-Hermelink HK, Hasenclever D, Löffler M. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009 Sep 20;27(27):4548-54. Epub 2009 Aug 24. link to original article PubMed
    3. Pooled update: von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. link to original article PubMed
  3. GITIL/FIL HD2000: Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, Montanini A, La Sala A, Merli F, Stelitano C, Pozzi S, Scalone R, Di Renzo N, Musto P, Baldini L, Cervetti G, Angrilli F, Mazza P, Brugiatelli M, Gobbi PG; HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009 Feb 10;27(5):805-11. Epub 2009 Jan 5. link to original article PubMed NCT00443677
    1. Update: Merli F, Luminari S, Gobbi PG, Cascavilla N, Mammi C, Ilariucci F, Stelitano C, Musso M, Baldini L, Galimberti S, Angrilli F, Polimeno G, Scalzulli PR, Ferrari A, Marcheselli L, Federico M. Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced Hodgkin lymphoma: a study by Fondazione Italiana Linfomi. J Clin Oncol. 2016 Apr 10;34(11):1175-81. Epub 2015 Dec 28. link to original article PubMed

BEACOPP-14

BEACOPP-14: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone, 14-day course

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sieber et al. 2003 1997-2000 Phase 2
Engert et al. 2012 (GHSG HD15) 2003-2008 Phase 3 (E-esc) 1. Escalated BEACOPP x 8 Not reported
2. Escalated BEACOPP x 6 Non-inferior FFTF (primary endpoint)

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Filgrastim (Neupogen) by the following weight-based criteria:
    • Less than 75 kg: 300 mcg SC once per day on days 8 to 13
    • 75 kg or more: 480 mcg SC once per day on days 8 to 13

14-day cycle for 8 cycles

References

  1. Sieber M, Bredenfeld H, Josting A, Reineke T, Rueffer U, Koch T, Naumann R, Boissevain F, Koch P, Worst P, Soekler M, Eich H, Müller-Hermelink HK, Franklin J, Paulus U, Wolf J, Engert A, Diehl V; German Hodgkin's Lymphoma Study Group. 14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 2003 May 1;21(9):1734-9. link to original article contains dosing details in manuscript PubMed
  2. GHSG HD15: Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, Zijlstra J, Král Z, Fuchs M, Hallek M, Kanz L, Döhner H, Dörken B, Engel N, Topp M, Klutmann S, Amthauer H, Bockisch A, Kluge R, Kratochwil C, Schober O, Greil R, Andreesen R, Kneba M, Pfreundschuh M, Stein H, Eich HT, Müller RP, Dietlein M, Borchmann P, Diehl V; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012 May 12;379(9828):1791-9. Epub 2012 Apr 4. Erratum in: Lancet. 2012 May 12;379(9828):1790. link to original article PubMed ISRCTN32443041

eBEACOPP

eBEACOPP: escalated Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
escBEACOPP: escalated Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
BEACOPP(escalated): Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone, escalated dose

Regimen variant #1, 2 cycles with response adaptation

Study Dates of enrollment Evidence
Borchmann et al. 2017 (GHSG HD18) 2008-2011 Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 2 cycles

Subsequent treatment

  • GHSG HD18, PET-negative, prior to June 2011: eBEACOPP continuation x 4 (6 total) versus eBEACOPP continuation x 6 (8 total)
  • GHSG HD18, PET-negative, after June 2011: eBEACOPP continuation x 2 (4 total) versus eBEACOPP continuation x 4 (6 total)
  • GHSG HD18, PET-positive, prior to June 2011: eBEACOPP continuation x 6 (8 total) versus R-eBEACOPP intensification x 6
  • GHSG HD18, PET-positive, after June 2011: eBEACOPP continuation x 4 (6 total)


Regimen variant #2, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borchmann et al. 2017 (GHSG HD18) 2008-2011 Phase 3 (C) 1. eBEACOPP x 6
2. eBEACOPP x 8 		Non-inferior PFS1

1Reported efficacy for GHSG HD18 is based on the 2017 update.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Filgrastim (Neupogen) 300 mcg SC once per day, starting day 8, continues until ANC greater than 1000/μL for 3 consecutive days

21-day cycle for 4 cycles


Regimen variant #3, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Engert et al. 2012 (GHSG HD15) 2003-2008 Phase 3 (E-de-esc) 1. BEACOPP-14 Non-inferior FFTF (primary endpoint)
2. eBEACOPP x 8 Seems to have superior OS (secondary endpoint)
Borchmann et al. 2017 (GHSG HD18) 2008-2011 Phase 3 (C) 1. eBEACOPP x 4
2. eBEACOPP x 8 		Non-inferior PFS1
Casasnovas et al. 2019 (AHL2011) 2011-2014 Phase 3 (C) PET-adapted therapy Inconclusive whether non-inferior PFS

1Reported efficacy for GHSG HD18 is based on the 2017 update.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles


Regimen variant #4, 8 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Diehl et al. 1998 (GHSG HD9) 1993-1998 Phase 3 (E-esc) 1. BEACOPP Superior FFTF
2. COPP/ABVD Seems to have superior OS
Borchmann et al. 2011 (GHSG HD12) 1999-2003 Phase 3 (C) BEACOPP4+4 Non-inferior OS1
Engert et al. 2012 (GHSG HD15) 2003-2008 Phase 3 (C) 1. BEACOPP-14 Not reported
2. eBEACOPP x 6 Seems to have inferior OS
Borchmann et al. 2017 (GHSG HD18) 2008-2011 Phase 3 (C) 1. eBEACOPP x 4
2. eBEACOPP x 6 		Non-inferior PFS2

1Reported efficacy for GHSG HD12 is based on the 2018 pooled update. 2Reported efficacy for GHSG HD18 is based on the 2017 update.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 8 cycles

Subsequent treatment

References

  1. GHSG HD9: Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rueffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Duehmke E, Georgii A, Loeffler M. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 1998 Dec;16(12):3810-21. link to original articlecontains dosing details in manuscript PubMed
    1. Update: Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003 Jun 12;348(24):2386-95. Erratum in: N Engl J Med. 2005 Aug 18;353(7):744. link to original article contains dosing details in abstract PubMed
    2. Update: Engert A, Diehl V, Franklin J, Lohri A, Dörken B, Ludwig WD, Koch P, Hänel M, Pfreundschuh M, Wilhelm M, Trümper L, Aulitzky WE, Bentz M, Rummel M, Sezer O, Müller-Hermelink HK, Hasenclever D, Löffler M. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009 Sep 20;27(27):4548-54. Epub 2009 Aug 24. link to original article PubMed
    3. Pooled update: von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. link to original article PubMed
  2. GITIL/FIL HD2000: Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, Montanini A, La Sala A, Merli F, Stelitano C, Pozzi S, Scalone R, Di Renzo N, Musto P, Baldini L, Cervetti G, Angrilli F, Mazza P, Brugiatelli M, Gobbi PG; HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009 Feb 10;27(5):805-11. Epub 2009 Jan 5. link to original article PubMed NCT00443677
    1. Update: Merli F, Luminari S, Gobbi PG, Cascavilla N, Mammi C, Ilariucci F, Stelitano C, Musso M, Baldini L, Galimberti S, Angrilli F, Polimeno G, Scalzulli PR, Ferrari A, Marcheselli L, Federico M. Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced Hodgkin lymphoma: a study by Fondazione Italiana Linfomi. J Clin Oncol. 2016 Apr 10;34(11):1175-81. Epub 2015 Dec 28. link to original article PubMed
  3. GHSG HD12: Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. link to original article PubMed NCT00265031
    1. Pooled update: von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. link to original article PubMed
  4. GHSG HD15: Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, Zijlstra J, Král Z, Fuchs M, Hallek M, Kanz L, Döhner H, Dörken B, Engel N, Topp M, Klutmann S, Amthauer H, Bockisch A, Kluge R, Kratochwil C, Schober O, Greil R, Andreesen R, Kneba M, Pfreundschuh M, Stein H, Eich HT, Müller RP, Dietlein M, Borchmann P, Diehl V; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012 May 12;379(9828):1791-9. Epub 2012 Apr 4. Erratum in: Lancet. 2012 May 12;379(9828):1790. link to original article PubMed ISRCTN32443041
  5. GHSG HD18: Borchmann P, Haverkamp H, Lohri A, Mey U, Kreissl S, Greil R, Markova J, Feuring-Buske M, Meissner J, Dührsen U, Ostermann H, Keller U, Maschmeyer G, Kuhnert G, Dietlein M, Kobe C, Eich H, Baues C, Stein H, Fuchs M, Diehl V, Engert A. Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPP(escalated) alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol. 2017 Apr;18(4):454-463. Epub 2017 Feb 22. link to original article PubMed NCT00515554
    1. Update: Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA, Zijlstra JM, Markova J, Meissner J, Feuring-Buske M, Hüttmann A, Dierlamm J, Soekler M, Beck HJ, Willenbacher W, Ludwig WD, Pabst T, Topp MS, Hitz F, Bentz M, Keller UB, Kühnhardt D, Ostermann H, Schmitz N, Hertenstein B, Aulitzky W, Maschmeyer G, Vieler T, Eich H, Baues C, Stein H, Fuchs M, Kuhnert G, Diehl V, Dietlein M, Engert A. PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2017 Dec 23;390(10114):2790-2802. Epub 2017 Oct 20. link to original article PubMed
    2. Update: Kreissl S, Goergen H, Buehnen I, Kobe C, Moccia A, Greil R, Eichenauer DA, Zijlstra JM, Markova J, Meissner J, Feuring-Buske M, Soekler M, Beck HJ, Willenbacher W, Ludwig WD, Pabst T, Topp MS, Hitz F, Bentz M, Keller UB, Kühnhardt D, Ostermann H, Hertenstein B, Aulitzky W, Maschmeyer G, Vieler T, Eich H, Baues C, Stein H, Fuchs M, Diehl V, Dietlein M, Engert A, Borchmann P; German Hodgkin Study Group. PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8(6):e398-e409. link to original article PubMed
  6. AHL2011: Casasnovas RO, Bouabdallah R, Brice P, Lazarovici J, Ghesquieres H, Stamatoullas A, Dupuis J, Gac AC, Gastinne T, Joly B, Bouabdallah K, Nicolas-Virelizier E, Feugier P, Morschhauser F, Delarue R, Farhat H, Quittet P, Berriolo-Riedinger A, Tempescul A, Edeline V, Maisonneuve H, Fornecker LM, Lamy T, Delmer A, Dartigues P, Martin L, André M, Mounier N, Traverse-Glehen A, Meignan M. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2019 Feb;20(2):202-215. Epub 2019 Jan 15. link to original article contains dosing details in abstract PubMed NCT01358747

eBEACOPP-BEACOPP

eBEACOPP-BEACOPP: escalated Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone followed by Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
BEACOPP4+4

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borchmann et al. 2011 (GHSG HD12) 1999-2003 Phase 3 (E-de-esc) eBEACOPP x 8 Non-inferior OS1 (secondary endpoint)
Viviani et al. 2011 (GSM-HD) 2000-2007 Phase 3 (E-esc) ABVD x 8 Seems to have superior FFFP (primary endpoint)
Carde et al. 2016 (EORTC 20012) 2002-2010 Phase 3 (E-esc) ABVD x 8 Did not meet primary endpoint of EFS
Mounier et al. 2014 (LYSA H34) 2003-2008 Phase 3 (E-esc) ABVD x 8 Might have superior EFS (primary endpoint)

1Reported efficacy for GHSG HD12 is based on the 2018 pooled update.

Chemotherapy, eBEACOPP portion (cycles 1 to 4)

Chemotherapy, BEACOPP portion (cycles 5 to 8)

Glucocorticoid therapy, both portions (cycles 1 to 8)

Supportive therapy, both portions (cycles 1 to 8)

  • Filgrastim (Neupogen) 300 mcg SC once per day, starting day 8, continues until ANC greater than 1000/μL for 3 consecutive days (GSM-HD) or until day 14 (LYSA H34)

21-day cycle for 8 cycles

Subsequent treatment


References

  1. GSM-HD: Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM, Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM, Pregno P, Gotti M, Gallamini A, Rota Scalabrini D, Bonadonna G, Gianni AM; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203-12. link to original article contains dosing details in manuscript PubMed NCT01251107
  2. GHSG HD12: Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. link to original article PubMed NCT00265031
    1. Pooled update: von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. link to original article PubMed
  3. LYSA H34: Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M, Gabarre J, Casasnovas O, Jaubert J, Colin P, Delmer A, Devidas A, Bachy E, Nicolas-Virelizier E, Aoudjhane A, Humbrecht C, Andre M, Carde P; Lymphoma Study Association. ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014 Aug;25(8):1622-8. Epub 2014 May 14. link to original article contains dosing details in manuscript PubMed RECF0219
  4. EORTC 20012: Carde P, Karrasch M, Fortpied C, Brice P, Khaled H, Casasnovas O, Caillot D, Gaillard I, Bologna S, Ferme C, Lugtenburg PJ, Morschhauser F, Aurer I, Coiffier B, Meyer R, Seftel M, Wolf M, Glimelius B, Sureda A, Mounier N. Eight cycles of ABVD versus four cycles of BEACOPPescalated plus four cycles of BEACOPPbaseline in stage III to IV, International Prognostic Score ≥ 3, high-risk Hodgkin lymphoma: First results of the phase III EORTC 20012 Intergroup trial. J Clin Oncol. 2016 Jun 10;34(17):2028-36. Epub 2016 Apr 25. link to original article contains dosing details in manuscript PubMed NCT00049595

C-MOPP/ABV

C-MOPP/ABV: CyclophosphaMide, Oncovin (Vincristine), Procarbazine, Prednisone, Adriamycin (Doxorubicin), Bleomycin, Vinblastine

Regimen

Study Dates of enrollment Evidence
Montoto et al. 2000 1992-06 to 1998-04 Phase 2

Chemotherapy

Glucocorticoid therapy

28-day cycle for 8 cycles

Subsequent treatment

  • 2500 to 4000 cGy of radiation therapy consolidation given over extended fields (mantle or inverted "Y" type) to patients with bulky disease or ones with residual disease after completion of chemotherapy

References

  1. Montoto S, Camós M, López-Guillermo A, Bosch F, Cervantes F, Blandé J, Esteve J, Cobo F, Nomdedeu B, Campo E, Montserrat E. Hybrid chemotherapy consisting of cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (C-MOPP/ABV) as first-line treatment for patients with advanced Hodgkin disease. Cancer. 2000 May 1;88(9):2142-8. link to original article contains dosing details in abstract PubMed

MOPP

MOPP: Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen variant #1, 8 cycles, prednisone 25 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Somers et al. 1994 1981-1986 Phase 3 (C) MOPP/ABVD Seems to have inferior FFS

Chemotherapy

Glucocorticoid therapy

28-day cycle for 8 cycles


Regimen variant #2, capped vincristine

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Canellos et al. 1992 (CALGB 8251) 1982-NR Phase 3 (C) 1. ABVD Seems to have inferior EFS1
2. MOPP/ABVD Seems to have inferior EFS1

1Reported efficacy is based on the 2009 update.

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 to 8 cycles


Regimen variant #3, uncapped vincristine

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Devita et al. 1970 1964-1967 Phase 2
Stutzman & Glidewell 1973 1967-1969 Phase 3 (E-switch-ic) 1. ALB
2. SEQ 		Superior ORR
Cooper et al. 1980 1972-1975 Phase 3 (C) 1. COPP Did not meet endpoint of OS
2. CVPP Seems to have inferior CR rate
3. MVPP Did not meet endpoint of OS
Bonadonna et al. 1975 1973-04 to 1974-01 Phase 3 (C) ABVD Did not meet efficacy endpoints
Santoro et al. 1982 1974-1980 Phase 3 (C) MOPP/ABVD Inferior PFS
Santoro et al. 1987 1974-1982 Phase 3 (C) ABVD Seems to have inferior OS
Longo et al. 1991a 1978-1988 Phase 3 (C) MOPP/CABS Did not meet endpoint of OS

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 to 8 cycles


Regimen variant #4, BNLI variant

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jelliffe 1976 1970-1975 Phase 3 (C) TNI Inferior DFS
Hancock 1986 1979-NR Phase 3 (C) LOPP Did not meet primary endpoint of OS

Chemotherapy

Glucocorticoid therapy

28-day cycle for at least 6 cycles

References

  1. Devita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med. 1970 Dec;73(6):881-95. link to original article contains dosing details in abstract PubMed content property of HemOnc.org
  2. Stutzman L, Glidewell O; Acute Leukemia Group B. Multiple chemotherapeutic agents for Hodgkin disease: comparison of three routines: a cooperative study by Acute Leukemia Group B. JAMA. 1973 Sep 3;225(10):1202-11. link to original article contains dosing details in manuscript PubMed
  3. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975 Jul;36(1):252-9. link to original article PubMed
  4. Jelliffe AM; British National Lymphoma Investigation. Initial treatment of stage IIIA Hodgkin's disease: comparison of radiotherapy with combined chemotherapy. Lancet. 1976 Nov 6;2(7993):991-5. link to original article contains dosing details in manuscript PubMed
  5. Cooper MR, Pajak TF, Nissen NI, Stutzman L, Brunner K, Cuttner J, Falkson G, Grunwald H, Bank A, Leone L, Seligman BR, Silver RT, Weiss RB, Haurani F, Blom J, Spurr CL, Glidewell OJ, Gottlieb AJ, Holland JF. A new effective four-drug combination of CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) (NSC-79038), vinblastine, prednisone, and procarbazine for the treatment of advanced Hodgkin's disease. Cancer. 1980 Aug 15;46(4):654-62. link to original article PubMed
  6. Santoro A, Bonadonna G, Bonfante V, Valagussa P. Alternating drug combinations in the treatment of advanced Hodgkin's disease. N Engl J Med. 1982 Apr 1;306(13):770-5. link to original article PubMed
    1. Update: Bonadonna G, Valagussa P, Santoro A. Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin's disease: a report of 8-year results. Ann Intern Med. 1986 Jun;104(6):739-46. link to original article PubMed
  7. Hancock BW; British National Lymphoma Investigation. Randomised study of MOPP (mustine, Oncovin, procarbazine, prednisone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin's disease. Radiother Oncol. 1986 Nov;7(3):215-21. link to original article PubMed
    1. Update: Hancock BW, Vaughan Hudson G, Vaughan Hudson B, Haybittle JL, Bennett MH, MacLennan KA, Jelliffe AM; BNLI. British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin's disease--long term results. Br J Cancer. 1991 Apr;63(4):579-82. link to original article link to PMC article PubMed
  8. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnoni AM, Bonfante V, Musumeci R, Crippa F, Tesoro-Tess JD, Banfi A. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol. 1987 Jan;5(1):27-37. link to original article PubMed
  9. Longo DL, Duffey PL, DeVita VT Jr, Wiernik PH, Hubbard SM, Phares JC, Bastian AW, Jaffe ES, Young RC. Treatment of advanced-stage Hodgkin's disease: alternating noncrossresistant MOPP/CABS is not superior to MOPP. J Clin Oncol. 1991 Aug;9(8):1409-20. link to original article PubMed
  10. CALGB 8251: Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. link to original article does not contain dosing details PubMed
    1. Update: Canellos GP, Niedzwiecki D. Long-term follow-up of Hodgkin's disease trial. N Engl J Med. 2002 May 2;346(18):1417-8. link to original article PubMed
    2. Update: Canellos GP, Niedzwiecki D, Johnson JL. Long-term follow-up of survival in Hodgkin's lymphoma. N Engl J Med. 2009 Dec 10;361(24):2390-1. link to original article PubMed
  11. Somers R, Carde P, Henry-Amar M, Tarayre M, Thomas J, Hagenbeek A, Monconduit M, de Pauw BE, Breed WP, Verdonck L, Burgers JMV, Eghbali H, Zittoun R; EORTC Lymphoma Cooperative Group. A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organisation for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial. J Clin Oncol. 1994 Feb;12(2):279-87. link to original article contains dosing details in manuscript PubMed

MOPP-ABV

MOPP-ABV: Mustargen (Mechlorethamine), Oncovin (Vincristine), Procarbazine, Prednisone, Adriamycin (Doxorubicin), Bleomycin, Vinblastine
MOPP-ABV hybrid

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Klimo & Connors 1985 1980-1984 Phase 2
Connor et al. 1997 (NCIC-CTG HD4) 1984-1989 Phase 3 (E-de-esc) MOPP/ABVD Did not meet primary endpoint of FFS24
Glick et al. 1998 (ECOG E4486) 1987-1989 Phase 3 (E-switch-ic) MOPP x 6, then ABVD x 3 Seems to have superior OS
Duggan et al. 2003 (CALGB-8952) NR-1995 Phase 3 (E-esc) ABVD Did not meet primary endpoint of CR rate
Aleman et al. 2003 (EORTC 20884) 1989-2000 Non-randomized part of phase 3 RCT

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 to 8 cycles

Subsequent treatment

References

  1. Klimo P, Connors JM. MOPP/ABV hybrid program: combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin's disease. J Clin Oncol. 1985 Sep;3(9):1174-82. link to original article contains dosing details in manuscript PubMed
  2. NCIC-CTG HD4: Connors JM, Klimo P, Adams G, Burns BF, Cooper I, Meyer RM, O'Reilly SE, Pater J, Quirt I, Sadura A, Shustik C, Skillings J, Sutcliffe S, Verma S, Yoshida S, Zee B. Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol. 1997 Apr;15(4):1638-45. Erratum in: J Clin Oncol 1997 Jul;15(7):2762. link to original article PubMed
  3. ECOG E4486: Glick JH, Young ML, Harrington D, Schilsky RL, Beck T, Neiman R, Fisher RI, Peterson BA, Oken MM. MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial. J Clin Oncol. 1998 Jan;16(1):19-26. link to original article PubMed
  4. CALGB-8952: Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, Canellos GP, Peterson BA. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol. 2003 Feb 15;21(4):607-14. link to original article PubMed
  5. EORTC 20884: Aleman BM, Raemaekers JM, Tirelli U, Bortolus R, van 't Veer MB, Lybeert ML, Keuning JJ, Carde P, Girinsky T, van der Maazen RW, Tomsic R, Vovk M, van Hoof A, Demeestere G, Lugtenburg PJ, Thomas J, Schroyens W, De Boeck K, Baars JW, Kluin-Nelemans JC, Carrie C, Aoudjhane M, Bron D, Eghbali H, Smit WG, Meerwaldt JH, Hagenbeek A, Pinna A, Henry-Amar M; EORTC Lymphoma Group. Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med. 2003 Jun 12;348(24):2396-406. link to original article contains dosing details in manuscript PubMed

RABVD

RABVD: Rituximab, Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen variant #1

Study Dates of enrollment Evidence
Younes et al. 2012 (MDACC ID00-218) 2001-2007 Phase 2

Targeted therapy

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

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #2

Study Dates of enrollment Evidence
Kasamon et al. 2012 (J0615) 2006-NR Phase 2

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Pre-phase: 375 mg/m2 IV once one week prior to cycle 1 of ABVD
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2, 4, 6: 375 mg/m2 IV once on day 1

Chemotherapy

28-day cycle for 6 to 8 cycles

References

  1. MDACC ID00-218: Younes A, Oki Y, McLaughlin P, Copeland AR, Goy A, Pro B, Feng L, Yuan Y, Chuang HH, Macapinlac HA, Hagemeister F, Romaguera J, Samaniego F, Fanale MA, Dabaja BS, Rodriguez MA, Dang N, Kwak LW, Neelapu SS, Fayad LE. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood. 2012 May 3;119(18):4123-8. Epub 2012 Feb 27. link to original article contains dosing details in abstract link to PMC article PubMed NCT00504504
  2. J0615: Kasamon YL, Jacene HA, Gocke CD, Swinnen LJ, Gladstone DE, Perkins B, Link BK, Popplewell LL, Habermann TM, Herman JM, Matsui WH, Jones RJ, Ambinder RF. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012 May 3;119(18):4129-32. Epub 2012 Feb 16. link to original article contains partial protocol link to PMC article PubMed NCT00369681

Stanford V

Regimen variant #1, younger patients

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bartlett et al. 1995 1989-NR Non-randomized
Horning et al. 2000 (ECOG E1492) 1992-1995 Phase 2
Hoskin et al. 2009 (BNLI STANFORDV) 1998-2006 Phase 3 (E-esc) ABVD Did not meet primary endpoint of PFS
Gordon et al. 2012 (ECOG E2496) 1999-2006 Phase 3 (E-esc) ABVD Did not meet primary endpoint of FFS

Eligibility criteria

  • 50 years old or younger

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) as follows:
    • Cycles 1 & 2: 40 mg/m2 PO every other day
    • Cycle 3, week 1 (week 9): 40 mg/m2 PO every other day
    • Cycle 3, week 2 (week 10): 30 mg/m2 PO every other day
    • Cycle 3, week 3 (week 11): 20 mg/m2 PO every other day
    • Cycle 3, week 4 (week 12): 10 mg/m2 PO every other day

Supportive therapy

  • If dose reduction or delay occurred at any time during chemotherapy, Filgrastim (Neupogen) 5 mcg/kg SC once per day x 5 days (starting 48 hours after myelosuppressive chemotherapy) should be given after all subsequent day 1 and 15 doses of chemotherapy. It was not precisely specified when to discontinue filgrastim.
  • Ranitidine (Zantac) 150 mg PO twice per day throughout the course of treatment
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day throughout the course of treatment
  • Acyclovir (Zovirax) 200 mg PO three times per day throughout the course of treatment
  • Ketoconazole (Nizoral) 200 mg PO once per day throughout the course of treatment; note: this may be optional--Horning SJ et al. J Clin Oncol (2000) listed this as a prophylactic medication, but Horning SJ et al. J Clin Oncol (2002) did not list this when prophylactic medications were specifically listed.

28-day cycle for 3 cycles

Subsequent treatment

  • IFRT x 3600 cGy consolidation, started 2 to 4 weeks after chemotherapy is complete and is given to sites of disease greater than or equal to 5 cm and/or to macroscopic nodules in the spleen.

Dose and schedule modifications

  • Doses of doxorubicin, vinblastine, mechlorethamine, and etoposide were reduced to 65% of the original dose if the ANC on the day of treatment was 500 to 1000/μL. If ANC was less than 500/μL on the day of treatment, therapy was delayed for 1 week, and therapy resumed the following week at the dose indicated by the ANC. As noted above, filgrastim was incorporated into all subsequent treatments if there were any dose reductions or delays.


Regimen variant #2, older patients

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bartlett et al. 1995 1989-NR Non-randomized
Horning et al. 2000 (ECOG E1492) 1992-1995 Phase 2
Hoskin et al. 2009 (BNLI STANFORDV) 1998-2006 Phase 3 (E-esc) ABVD Did not meet primary endpoint of PFS
Gordon et al. 2012 (ECOG E2496) 1999-2006 Phase 3 (E-esc) ABVD Did not meet primary endpoint of FFS

Eligibility criteria

  • Older than 50 years old

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) as follows:
    • Cycles 1 & 2: 40 mg/m2 PO every other day
    • Cycle 3, week 1 (week 9): 40 mg/m2 PO every other day
    • Cycle 3, week 2 (week 10): 30 mg/m2 PO every other day
    • Cycle 3, week 3 (week 11): 20 mg/m2 PO every other day
    • Cycle 3, week 4 (week 12): 10 mg/m2 PO every other day

Supportive therapy

  • If dose reduction or delay occurred at any time during chemotherapy, Filgrastim (Neupogen) 5 mcg/kg SC once per day x 5 days (starting 48 hours after myelosuppressive chemotherapy) should be given after all subsequent day 1 and 15 doses of chemotherapy. It was not precisely specified when to discontinue filgrastim.
  • Ranitidine (Zantac) 150 mg PO twice per day throughout the course of treatment
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day throughout the course of treatment
  • Acyclovir (Zovirax) 200 mg PO three times per day throughout the course of treatment
  • Ketoconazole (Nizoral) 200 mg PO once per day throughout the course of treatment; note: this may be optional--Horning SJ et al. J Clin Oncol (2000) listed this as a prophylactic medication, but Horning SJ et al. J Clin Oncol (2002) did not list this when prophylactic medications were specifically listed.

28-day cycle for 3 cycles

Subsequent treatment

  • IFRT x 3600 cGy consolidation, started 2 to 4 weeks after chemotherapy is complete and is given to sites of disease greater than or equal to 5 cm and/or to macroscopic nodules in the spleen.

Dose and schedule modifications

  • Doses of doxorubicin, vinblastine, mechlorethamine, and etoposide were reduced to 65% of the original dose if the ANC on the day of treatment was 500 to 1000/μL. If ANC was less than 500/μL on the day of treatment, therapy was delayed for 1 week, and therapy resumed the following week at the dose indicated by the ANC. As noted above, filgrastim was incorporated into all subsequent treatments if there were any dose reductions or delays.

References

  1. Bartlett NL, Rosenberg SA, Hoppe RT, Hancock SL, Horning SJ. Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin's disease: a preliminary report. J Clin Oncol. 1995 May;13(5):1080-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: mature results of a prospective clinical trial. J Clin Oncol. 2002 Feb 1;20(3):630-7. link to original article PubMed
  2. ECOG E1492: Horning SJ, Williams J, Bartlett NL, Bennett JM, Hoppe RT, Neuberg D, Cassileth P. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin's disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol. 2000 Mar;18(5):972-80. link to original article contains dosing details in abstract PubMed
  3. Gobbi PG, Levis A, Chisesi T, Broglia C, Vitolo U, Stelitano C, Pavone V, Cavanna L, Santini G, Merli F, Liberati M, Baldini L, Deliliers GL, Angelucci E, Bordonaro R, Federico M; Intergruppo Italiano Linfomi. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol. 2005 Dec 20;23(36):9198-207. Epub 2005 Sep 19. link to original article PubMed
    1. Update: Chisesi T, Bellei M, Luminari S, Montanini A, Marcheselli L, Levis A, Gobbi P, Vitolo U, Stelitano C, Pavone V, Merli F, Liberati M, Baldini L, Bordonaro R, Pesce EA, Federico M. Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol. 2011 Nov 10;29(32):4227-33. Epub 2011 Oct 11. link to original article PubMed
  4. BNLI STANFORDV: Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW, Smith P, Qian W, Patrick P, Popova B, Pettitt A, Cunningham D, Pettengell R, Sweetenham J, Linch D, Johnson PW. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009 Nov 10;27(32):5390-6. Epub 2009 Sep 8. link to original article PubMed NCT00041210
  5. Retrospective: Edwards-Bennett SM, Jacks LM, Moskowitz CH, Wu EJ, Zhang Z, Noy A, Portlock CS, Straus DJ, Zelenetz AD, Yahalom J. Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Ann Oncol. 2010 Mar;21(3):574-81. link to original article PubMed
  6. ECOG E2496: Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: An Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article link to PMC article PubMed NCT00003389
    1. Subgroup analysis: Evens AM, Hong F, Gordon LI, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Gospodarowicz M, Cheson BD, Stiff PJ, Advani R, Miller TP, Hoppe RT, Kahl BS, Horning SJ. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013 Apr;161(1):76-86. Epub 2013 Jan 29. link to original article link to PMC article PubMed
    2. Subgroup analysis: Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin lymphoma: a subset analysis of the North American Intergroup E2496 trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol link to PMC article PubMed

VEBEP

VEBEP: Vepesid (Etoposide), Epirubicin, Bleomycin, Endoxan (Cyclophosphamide), Prednisolone

Regimen

Study Dates of enrollment Evidence
Viviani et al. 1999 1990-09 to 1993-03 Phase 2

Chemotherapy

Glucocorticoid therapy

References

  1. Viviani S, Bonfante V, Santoro A, Zanini M, Devizzi L, Di Russo AD, Soncini F, Villani F, Ragni G, Valagussa P, Bonadonna G. Long-term results of an intensive regimen: VEBEP plus involved-field radiotherapy in advanced Hodgkin's disease. Cancer J Sci Am. 1999 Sep-Oct;5(5):275-82. PubMed

Untreated, elderly

BEACOPP

BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ballova et al. 2005 (GHSG HD9elderly) 1993-1998 Phase 3 (E-switch-ic) COPP/ABVD Did not meet efficacy endpoints

Note: this is technically "BEACOPP II." The original "BEACOPP I" is detailed in Diehl et al. 1997 but is of historical interest, only.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 8 cycles

References

  1. GHSG HD9elderly: Ballova V, Rüffer JU, Haverkamp H, Pfistner B, Müller-Hermelink HK, Dühmke E, Worst P, Wilhelmy M, Naumann R, Hentrich M, Eich HT, Josting A, Löffler M, Diehl V, Engert A. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005 Jan;16(1):124-31. link to original articlecontains dosing details in abstract PubMed

Brentuximab vedotin monotherapy

Regimen variant #1, standard-dose

Study Dates of enrollment Evidence Efficacy
Forero-Torres et al. 2015 (SGN35-015mono) 2012-10 to 2015-03 Phase 2 ORR: 92%

Antibody-drug conjugate therapy

Supportive therapy

  • "according to institutional standards"

21-day cycle for up to 16 cycles, with continuing treatment allowed for those deriving clinical benefit


Regimen variant #2, reduced-dose

Study Dates of enrollment Evidence
Forero-Torres et al. 2015 (SGN35-015mono) 2012-10 to 2015-03 Phase 2, fewer than 20 pts in this subgroup

Note: This was the starting dose for severe renal impairment (eGFR less than 30 mL/min/1.73m2) and also the dose reduction for toxicities. While described as a planned starting dose, no patients in the study actually had severe renal impairment.

Antibody-drug conjugate therapy

Supportive therapy

  • "according to institutional standards"

21-day cycle for up to 16 cycles, with continuing treatment allowed for those deriving clinical benefit

References

  1. SGN35-015mono: Forero-Torres A, Holkova B, Goldschmidt J, Chen R, Olsen G, Boccia RV, Bordoni RE, Friedberg JW, Sharman JP, Palanca-Wessels MC, Wang Y, Yasenchak CA. Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015 Dec 24;126(26):2798-804. Epub 2015 Sep 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01716806

Brentuximab vedotin & Dacarbazine

Regimen variant #1, standard-dose

Study Dates of enrollment Evidence Efficacy
Friedberg et al. 2017 (SGN35-015combo) 2014-02 to 2015-09 Phase 2 ORR: 100%

Antibody-drug conjugate therapy

Chemotherapy

21-day cycle for up to 16 cycles, with continuing treatment allowed for those deriving clinical benefit


Regimen variant #2, reduced-dose

Study Dates of enrollment Evidence Efficacy
Friedberg et al. 2017 (SGN35-015combo) 2014-02 to 2015-09 Phase 2, fewer than 20 pts in this subgroup ORR: 100%

Note: This is the starting dose for severe renal impairment (eGFR less than 30 mL/min/1.73m2). Only 2 patients in the study had severe renal impairment.

Antibody-drug conjugate therapy

Chemotherapy

21-day cycle for up to 16 cycles, with continuing treatment allowed for those deriving clinical benefit

References

  1. SGN35-015combo: Friedberg JW, Forero-Torres A, Bordoni RE, Cline VJM, Patel Donnelly D, Flynn PJ, Olsen G, Chen R, Fong A, Wang Y, Yasenchak CA. Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL. Blood. 2017 Dec 28;130(26):2829-2837. Epub 2017 Oct 16. link to original article contains dosing details in manuscript PubMed NCT01716806

ChlVPP

ChlVPP: Chllorambucil, Vinblastine, Procarbazine, Prednisone

Regimen

Study Evidence
Anderson 1995 Retrospective

Chemotherapy

Glucocorticoid therapy

28-day cycle to complete remission plus 2 cycles; minimum of 6 cycles and maximum of 8 cycles

References

  1. Retrospective: Druker BJ, Rosenthal DS, Canellos GP. Chlorambucil, vinblastine, procarbazine, and prednisone. An effective but less toxic regimen than MOPP for advanced-stage Hodgkin's disease. Cancer. 1989 Mar 15;63(6):1060-4. link to original article PubMed
  2. Case series: Selby P, Patel P, Milan S, Meldrum M, Mansi J, Mbidde E, Brada M, Perren T, Forgeson G, Gore M, Smith I, McElwain T. ChlVPP combination chemotherapy for Hodgkin's disease: long-term results. Br J Cancer. 1990 Aug;62(2):279-85. link to PMC article PubMed
  3. Retrospective: Anderson JR; International ChlVPP Treatment Group. ChlVPP therapy for Hodgkin's disease: experience of 960 patients. Ann Oncol. 1995 Feb;6(2):167-72. link to original article contains dosing details in abstract PubMed

ChlVPP/EVA

ChlVPP/EVA: Chllorambucil, Vinblastine, Procarbazine, Prednisone, Etoposide, Vincristine, Adriamycin (Doxorubicin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Radford et al. 1995 1984-1992 Phase 3 (E-esc) MVPP Superior PFS
Radford et al. 2002 1992-1996 Phase 3 (C) VAPEC-B Seems to have superior OS

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 cycles

References

  1. Radford JA, Crowther D, Rohatiner AZ, Ryder WD, Gupta RK, Oza A, Deakin DP, Arnott S, Wilkinson PM, James RD, Johnson RJ, Lister TA. Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, ChlVPP/EVA, in the initial treatment of Hodgkin's disease. J Clin Oncol. 1995 Sep;13(9):2379-85. link to original article PubMed
  2. Radford JA, Rohatiner AZ, Ryder WD, Deakin DP, Barbui T, Lucie NP, Rossi A, Dunlop DJ, Cowan RA, Wilkinson PM, Gupta RK, James RD, Shamash J, Chang J, Crowther D, Lister TA. ChlVPP/EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin's disease. J Clin Oncol. 2002 Jul 1;20(13):2988-94. link to original article contains dosing details in manuscript PubMed

PVAG

PVAG: Prednisone, Vinblastine, Adriamycin (Doxorubicin), Gemcitabine

Regimen

Study Dates of enrollment Evidence
Böll et al. 2011 (PVAG elderly) 2004-03 to 2007-07 Phase 2

Note: This trial was open to patients with early unfavorable disease, but 93% of patients on study had advanced disease.

Glucocorticoid therapy

Chemotherapy

21-day cycle for 6 to 8 cycles

Subsequent treatment

References

  1. PVAG elderly: Böll B, Bredenfeld H, Görgen H, Halbsguth T, Eich HT, Soekler M, Markova J, Keller U, Graeven U, Kremers S, Geissler M, Trenn G, Fuchs M, von Tresckow B, Eichenauer DA, Borchmann P, Engert A. Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood. 2011 Dec 8;118(24):6292-8. Epub 2011 Sep 13. link to original article contains dosing details in manuscript PubMed NCT00147875

VEPEMB

VEPEMB: Vinblastine, Endoxan (Cyclophosphamide), Procarbazine, Etoposide, Mitoxantrone, Bleomycin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Levis et al. 2004 1995-2001 Phase 2
Proctor et al. 2012 (SHIELD) NR Phase 2
Zallio et al. 2016 2002-2006 Phase 3 (E-de-esc) ABVD Might have inferior PFS (primary endpoint)

Note: this regimen includes prednisone, even though it is not spelled out in the acronym.

Chemotherapy

Glucocorticoid therapy

28-day cycle for 3 to 6 cycles

References

  1. Levis A, Anselmo AP, Ambrosetti A, Adamo F, Bertini M, Cavalieri E, Gavarotti P, Genua A, Liberati M, Pavone V, Pietrasanta D, Ricetti MM, Scalabrini DR, Salvi F, Vitolo U, Angelucci E, Boccadoro M, Gallo E, Mandelli F; Intergruppo Italiano Linfomi. VEPEMB in elderly Hodgkin's lymphoma patients: results from an Intergruppo Italiano Linfomi (IIL) study. Ann Oncol. 2004 Jan;15(1):123-8. link to original article PubMed
  2. SHIELD: Proctor SJ, Wilkinson J, Jones G, Watson GC, Lucraft HH, Mainou-Fowler T, Culligan D, Galloway MJ, Wood KM, McNally RJ, James PW, Goodlad JR. Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study. Blood. 2012 Jun 21;119(25):6005-15. Epub 2012 May 10. link to original article PubMed
  3. Zallio F, Tamiazzo S, Monagheddu C, Merli F, Ilariucci F, Stelitano C, Liberati AM, Mannina D, Vitolo U, Angelucci E, Rota Scalabrini D, Vallisa D, Bellei M, Bari A, Ciccone G, Salvi F, Levis A. Reduced intensity VEPEMB regimen compared with standard ABVD in elderly Hodgkin lymphoma patients: results from a randomized trial on behalf of the Fondazione Italiana Linfomi (FIL). Br J Haematol. 2016 Mar;172(6):879-88. Epub 2016 Jan 13. link to original article contains dosing details in manuscript PubMed

Consolidation after upfront therapy

Radiation therapy

RT: Radiation Therapy

Regimen variant #1, 2000 cGy of involved field RT (IFRT)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Engert et al. 2010 (GHSG HD10) 1998-2003 Phase 3 (E-de-esc) IFRT x 3000 cGy Did not meet primary endpoint of FFTF
Eich et al. 2010 (GHSG HD11) 1998-2003 Phase 3 (E-de-esc) IFRT x 3000 cGy Inconclusive whether non-inferior FFTF (primary endpoint)

Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.

Preceding treatment

Radiotherapy


Regimen variant #3, 2400 cGy of IFRT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aleman et al. 2003 (EORTC 20884) 1989-2000 Phase 3 (E-esc) Observation Did not meet primary endpoint of RFS36

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

Radiotherapy


Regimen variant #4, 3000 cGy of IFRT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aleman et al. 2003 (EORTC 20884) 1989-2000 Phase 3 (E-esc) Observation Did not meet primary endpoint of RFS36
Engert et al. 2003 (GHSG HD8) 1993-1998 Phase 3 (E-de-esc) EFRT x 3000 cGy + 1000 cGy boost Equivalent FFTF
Advani et al. 2013 (G4) 1995-2001 Non-randomized
Engert et al. 2010 (GHSG HD10) 1998-2003 Phase 3 (C) IFRT x 2000 cGy Did not meet primary endpoint of FFTF
Eich et al. 2010 (GHSG HD11) 1998-2003 Phase 3 (C) IFRT x 2000 cGy Inconclusive whether non-inferior FFTF (primary endpoint)
von Tresckow et al. 2012 (GHSG HD14) 2003-2008 Non-randomized part of phase 3 RCT
Behringer et al. 2014 (GHSG HD13) 2003-2009 Non-randomized part of phase 3 RCT
Radford et al. 2015 (UK NCRI RAPID) 2003-2010 Phase 3 (C) No further treatment Inconclusive whether non-inferior PFS36
Borchmann et al. 2021 (GHSG HD17) 2012-2017 Phase 3 (C) See link See link

Preceding treatment

Radiotherapy


Regimen variant #5, 3000 cGy of involved site RT (ISRT)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borchmann et al. 2011 (GHSG HD12) 1999-2003 Phase 3 (E-esc) Observation Might have superior 5-year FFTF (primary endpoint)
Kumar et al. 2016 (MSK 13-034) 2013-06 to 2015-02 Phase 2

Preceding treatment

Radiotherapy


Regimen variant #6, 3000 cGy of involved node RT (INRT) + 600 cGy boost

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) 2006-2009 Phase 3 (C) See link See link

Preceding treatment

  • EORTC/LYSA/FIL H10 F: Induction ABVD x 3
  • EORTC/LYSA/FIL H10 U: Induction ABVD x 4

Radiotherapy


Regimen variant #7, 3000 cGy of extended-field RT (EFRT) + 1000 cGy boost

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Engert et al. 2003 (GHSG HD8) 1993-1998 Phase 3 (C) IFRT x 3000 cGy + 1000 cGy boost Equivalent FFTF
Engert et al. 2007 (GHSG HD7) 1993-1998 Non-randomized part of phase 3 RCT

Preceding treatment

Radiotherapy


Regimen variant #8, 3500 cGy of subtotal nodal irradiation (STNI)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Meyer et al. 2005 (NCIC-CTG/ECOG HD.6 U) 1994-2002 Phase 3 (C) See link See link

Note: see link for use of STNI as definitive therapy.

Preceding treatment

  • NCIC-CTG/ECOG HD.6 U: Induction ABVD x 2

Radiotherapy


Regimen variant #9, 3600 cGy of IFRT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 2004 1990-1996 Phase 3 (E-de-esc) STNI x 3600 cGy Inconclusive whether non-inferior
Fermé et al. 2007 (EORTC-GELA H8-F) 1993-1999 Phase 3 (E-de-esc) See link See link
Fermé et al. 2007 (EORTC-GELA H8-U) 1993-1999 Phase 3 (C) See link See link
Gordon et al. 2012 (ECOG E2496) 1999-2006 Non-randomized part of phase 3 RCT

Preceding treatment

  • Bonadonna et al. 2004: Induction ABVD x 4, with CR
  • EORTC-GELA H8-F: Induction MOPP-ABV x 3, with CR
  • EORTC-GELA H8-U: Induction MOPP-ABV x 4 versus MOPP-ABV x 6, with CR
  • ECOG E2496: Induction ABVD x 6 to 8 versus Stanford V x 12 wk

Radiotherapy


Regimen variant #10, 3600 cGy of STNI

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 2004 1990-1996 Phase 3 (C) IFRT x 3600 cGy Inconclusive whether non-inferior

Preceding treatment

  • Induction ABVD x 4, with CR

Radiotherapy


Regimen variant #11, 3600 cGy of STNI + 400 cGy boost

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fermé et al. 2007 (EORTC-GELA H8-U) 1993-1999 Phase 3 (E-esc) See link See link

Preceding treatment

Radiotherapy


Regimen variant #12, 4000 cGy of IFRT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 2004 1990-1996 Phase 3 (E-de-esc) STNI x 4000 cGy Inconclusive whether non-inferior
Fermé et al. 2007 (EORTC-GELA H8-F) 1993-1999 Phase 3 (E-de-esc) See link See link
Fermé et al. 2007 (EORTC-GELA H8-U) 1993-1999 Phase 3 (C) See link See link

Preceding treatment

  • Bonadonna et al. 2004: Induction ABVD x 4, with CRu or PR
  • EORTC-GELA H8-F: Induction MOPP-ABV x 3, with PR
  • EORTC-GELA H8-U: Induction MOPP-ABV x 4 versus MOPP-ABV x 6, with PR

Radiotherapy


Regimen variant #13, 4000 cGy of STNI

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 2004 1990-1996 Phase 3 (C) IFRT x 4000 cGy Inconclusive whether non-inferior

Preceding treatment

  • Induction ABVD x 4, with CRu or PR

Radiotherapy

References

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  9. GHSG HD11: Eich HT, Diehl V, Görgen H, Pabst T, Markova J, Debus J, Ho A, Dörken B, Rank A, Grosu AL, Wiegel T, Karstens JH, Greil R, Willich N, Schmidberger H, Döhner H, Borchmann P, Müller-Hermelink HK, Müller RP, Engert A. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010 Sep 20;28(27):4199-206. Epub 2010 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00264953
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  10. GHSG HD12: Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. link to original article PubMed NCT00265031
    1. Pooled update: von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. link to original article PubMed
  11. GHSG HD14: von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. link to original article contains dosing details in manuscript PubMed ISRCTN04761296
  12. G4: Advani RH, Hoppe RT, Baer D, Mason J, Warnke R, Allen J, Daadi S, Rosenberg SA, Horning SJ. Efficacy of abbreviated Stanford V chemotherapy and involved-field radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial. Ann Oncol. 2013 Apr;24(4):1044-8. Epub 2012 Nov 7. link to original article contains limited protocol link to PMC article PubMed
  13. ECOG E2496: Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: An Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013 Feb 20;31(6):684-91. Epub 2012 Nov 26. link to original article link to PMC article PubMed NCT00003389
    1. Subgroup analysis: Evens AM, Hong F, Gordon LI, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Gospodarowicz M, Cheson BD, Stiff PJ, Advani R, Miller TP, Hoppe RT, Kahl BS, Horning SJ. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013 Apr;161(1):76-86. Epub 2013 Jan 29. link to original article link to PMC article PubMed
    2. Subgroup analysis: Advani RH, Hong F, Fisher RI, Bartlett NL, Robinson KS, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Gordon LI, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial comparing ABVD plus radiotherapy with the Stanford V regimen in patients with stages I or II locally extensive, bulky mediastinal Hodgkin lymphoma: a subset analysis of the North American Intergroup E2496 trial. J Clin Oncol. 2015 Jun 10;33(17):1936-42. Epub 2015 Apr 20. link to original article contains limited protocol link to PMC article PubMed
  14. EORTC/LYSA/FIL H10: Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains dosing details in abstract PubMed NCT00433433
    1. Update: André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. link to original article PubMed
    2. Update: Federico M, Fortpied C, Stepanishyna Y, Gotti M, van der Maazen R, Cristinelli C, Re A, Plattel W, Lazarovici J, Merli F, Specht L, Schiano de Colella JM, Hutchings M, Versari A, Edeline V, Stamatoulas A, Girinsky T, Ricardi U, Aleman B, Meulemans B, Tonino S, Raemaekers J, André M. Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma. J Clin Oncol. 2024 Jan 1;42(1):19-25. Epub 2023 Nov 15. link to original article link to PMC article PubMed
  15. GHSG HD13: Behringer K, Goergen H, Hitz F, Zijlstra JM, Greil R, Markova J, Sasse S, Fuchs M, Topp MS, Soekler M, Mathas S, Meissner J, Wilhelm M, Koch P, Lindemann HW, Schalk E, Semrau R, Kriz J, Vieler T, Bentz M, Lange E, Mahlberg R, Hassler A, Vogelhuber M, Hahn D, Mezger J, Krause SW, Skoetz N, Böll B, von Tresckow B, Diehl V, Hallek M, Borchmann P, Stein H, Eich H, Engert A; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015 Apr 11;385(9976):1418-27. Epub 2014 Dec 22. Erratum in: Lancet. 2015 Apr 11;385(9976):1396. link to original article PubMed ISRCTN63474366
    1. Pooled subgroup analysis: Böll B, Goergen H, Behringer K, Bröckelmann PJ, Hitz F, Kerkhoff A, Greil R, von Tresckow B, Eichenauer DA, Bürkle C, Borchmann S, Fuchs M, Diehl V, Engert A, Borchmann P. Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials. Blood. 2016 May 5;127(18):2189-92. Epub 2016 Feb 1. link to original article PubMed
  16. UK NCRI RAPID: Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. link to original article contains dosing details in abstract PubMed NCT00943423
  17. MSK 13-034: Kumar A, Casulo C, Yahalom J, Schöder H, Barr PM, Caron P, Chiu A, Constine LS, Drullinsky P, Friedberg JW, Gerecitano JF, Hamilton A, Hamlin PA, Horwitz SM, Jacob AG, Matasar MJ, McArthur GN, McCall SJ, Moskowitz AJ, Noy A, Palomba ML, Portlock CS, Straus DJ, VanderEls N, Verwys SL, Yang J, Younes A, Zelenetz AD, Zhang Z, Moskowitz CH. Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2016 Sep 15;128(11):1458-64. Epub 2016 Jul 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01868451
  18. GHSG HD17: Borchmann P, Plütschow A, Kobe C, Greil R, Meissner J, Topp MS, Ostermann H, Dierlamm J, Mohm J, Thiemer J, Sökler M, Kerkhoff A, Ahlborn M, Halbsguth TV, Martin S, Keller U, Balabanov S, Pabst T, Vogelhuber M, Hüttmann A, Wilhelm M, Zijlstra JM, Moccia A, Kuhnert G, Bröckelmann PJ, von Tresckow B, Fuchs M, Klimm B, Rosenwald A, Eich H, Baues C, Marnitz S, Hallek M, Diehl V, Dietlein M, Engert A. PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):223-234. link to original article PubMed NCT01356680

Relapsed or refractory, all lines of therapy

Note: most regimens in this section are salvage therapy, i.e., considered as part of a curative treatment approach, often prior to autologous or allogeneic HSCT. Some are for later line therapy and for transplant-ineligible patients and these are in the process of being moved to a new section, below.

ABVD

ABVD: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine

Regimen

Study Dates of enrollment Evidence
Radford et al. 2015 (UK NCRI RAPID) 2003-2010 Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

  • Induction ABVD x 3, with interim PET-CT showing Deauville score 3 to 5 refractory disease

Chemotherapy

28-day course

Subsequent treatment

References

  1. UK NCRI RAPID: Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. link to original article contains dosing details in abstract PubMed NCT00943423

BEACOPP-14 (Prednisolone)

BEACOPP-14: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisolone, 14-day course

Regimen

Study Dates of enrollment Evidence
Johnson et al. 2016 (RATHL) 2008-2012 Non-randomized part of phase 3 RCT

Note: unlike most BEACOPP regimens, this one uses prednisolone (not prednisone).

Preceding treatment

  • Induction ABVD x 2, with interim PET-CT showing Deauville score 4 or 5 refractory disease

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Growth factor support with ONE of the following:

14-day cycle for 4 to 6 cycles

References

  1. RATHL: Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, d'Amore F, Enblad G, Franceschetto A, Fulham M, Luminari S, O'Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016 Jun 23;374(25):2419-29. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00678327
    1. Update: Luminari S, Fossa A, Trotman J, Molin D, d'Amore F, Enblad G, Berkahn L, Barrington SF, Radford J, Federico M, Kirkwood AA, Johnson PWM. Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial. J Clin Oncol. 2024 Jan 1;42(1):13-18. Epub 2023 Oct 26. link to original article link to PMC article PubMed

BEACOPP

BEACOPP: Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone
BEACOPPbaseline

Regimen

Study Dates of enrollment Evidence
Gallamini et al. 2018 (GITIL/FIL HD 0607) 2008-2014 Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Chemotherapy

Glucocorticoid therapy

21-day cycle for 4 cycles

References

  1. GITIL/FIL HD 0607: Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mulé A, Picardi M, Romano A, Cantonetti M, La Nasa G, Trentin L, Bolis S, Rapezzi D, Battistini R, Gottardi D, Gavarotti P, Corradini P, Cimminiello M, Schiavotto C, Parvis G, Zanotti R, Gini G, Ferreri AJM, Viero P, Miglino M, Billio A, Avigdor A, Biggi A, Fallanca F, Ficola U, Gregianin M, Chiaravalloti A, Prosperini G, Bergesio F, Chauvie S, Pavoni C, Gianni AM, Rambaldi A. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018 Feb 10;36(5):454-462. Epub 2018 Jan 23. link to original article contains dosing details in supplement PubMed NCT00795613
    1. Update: Gallamini A, Rossi A, Patti C, Picardi M, Romano A, Cantonetti M, Oppi S, Viviani S, Bolis S, Trentin L, Gini G, Battistini R, Chauvie S, Sorasio R, Pavoni C, Zanotti R, Cimminiello M, Schiavotto C, Viero P, Mulé A, Fallanca F, Ficola U, Tarella C, Guerra L, Rambaldi A. Consolidation Radiotherapy Could Be Safely Omitted in Advanced Hodgkin Lymphoma With Large Nodal Mass in Complete Metabolic Response After ABVD: Final Analysis of the Randomized GITIL/FIL HD0607 Trial. J Clin Oncol. 2020 Nov 20;38(33):3905-3913. Epub 2020 Sep 18. Erratum in: J Clin Oncol. 2021 Jan 1;39(1):96. link to original article PubMed

eBEACOPP

eBEACOPP: escalated Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone

Regimen variant #1, 2 cycles

Study Dates of enrollment Evidence
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) 2006-2009 Non-randomized part of phase 3 RCT

Note: dosing is not described in the paper; this is the standard escalated BEACOPP as described elsewhere.

Preceding treatment

  • EORTC/LYSA/FIL H10 F: Induction ABVD x 2, with interim PET-CT showing Deauville score 3 to 5 refractory disease
  • EORTC/LYSA/FIL H10 U: Induction ABVD x 2, with interim PET-CT showing Deauville score 3 to 5 refractory disease

Chemotherapy

Glucocorticoid therapy

21-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borchmann et al. 2017 (GHSG HD18) 2008-2011 Non-randomized part of phase 3 RCT
Gallamini et al. 2018 (GITIL/FIL HD 0607) 2008-2014 Phase 3 (C) R-BEACOPP Did not meet primary endpoint of PFS

Note: patients in GHSG HD18 enrolled after June 2011 would receive a total of 6 cycles.

Preceding treatment

  • GHSG HD18: Induction eBEACOPP x 2, with positive interim PET-CT
  • GITIL/FIL HD 0607: Induction ABVD x 2, with positive interim PET-CT

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 4 cycles (see note)

Subsequent treatment

  • GITIL/FIL HD 0607, negative interim PET-CT: BEACOPP (baseline) de-intensification x 4
  • GITIL/FIL HD 0607, positive interim PET-CT: DHAP salvage


Regimen variant #3, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borchmann et al. 2017 (GHSG HD18) 2008-2011 Phase 3 (C) R-BEACOPPescalated Did not meet primary endpoint of PFS60
Press et al. 2016 (SWOG S0816) 2009-2012 Phase 2

Note: patients in GHSG HD18 enrolled prior to June 2011 would receive a total of 8 cycles.

Preceding treatment

  • SWOG S0816: Induction ABVD x 2, with interim PET-CT showing Deauville score 4 or 5 refractory disease
  • GHSG HD18: Induction eBEACOPP x 2, with positive interim PET-CT

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles

References

  1. EORTC/LYSA/FIL H10: Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains dosing details in abstract PubMed NCT00433433
    1. Update: André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. link to original article PubMed
    2. Update: Federico M, Fortpied C, Stepanishyna Y, Gotti M, van der Maazen R, Cristinelli C, Re A, Plattel W, Lazarovici J, Merli F, Specht L, Schiano de Colella JM, Hutchings M, Versari A, Edeline V, Stamatoulas A, Girinsky T, Ricardi U, Aleman B, Meulemans B, Tonino S, Raemaekers J, André M. Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma. J Clin Oncol. 2024 Jan 1;42(1):19-25. Epub 2023 Nov 15. link to original article link to PMC article PubMed
  2. SWOG S0816: Press OW, Li H, Schöder H, Straus DJ, Moskowitz CH, LeBlanc M, Rimsza LM, Bartlett NL, Evens AM, Mittra ES, LaCasce AS, Sweetenham JW, Barr PM, Fanale MA, Knopp MV, Noy A, Hsi ED, Cook JR, Lechowicz MJ, Gascoyne RD, Leonard JP, Kahl BS, Cheson BD, Fisher RI, Friedberg JW. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016 Jun 10;34(17):2020-7. Epub 2016 Apr 11. link to original article refers to original protocol link to PMC article PubMed NCT00822120
    1. Update: Stephens DM, Li H, Schöder H, Straus DJ, Moskowitz CH, LeBlanc M, Rimsza LM, Bartlett NL, Evens AM, LaCasce AS, Barr PM, Knopp MV, Hsi ED, Leonard JP, Kahl BS, Smith SM, Friedberg JW. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma. Blood. 2019 Oct 10;134(15):1238-1246. link to original article link to PMC article PubMed
  3. GHSG HD18: Borchmann P, Haverkamp H, Lohri A, Mey U, Kreissl S, Greil R, Markova J, Feuring-Buske M, Meissner J, Dührsen U, Ostermann H, Keller U, Maschmeyer G, Kuhnert G, Dietlein M, Kobe C, Eich H, Baues C, Stein H, Fuchs M, Diehl V, Engert A. Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPP(escalated) alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol. 2017 Apr;18(4):454-463. Epub 2017 Feb 22. link to original article PubMed NCT00515554
    1. Update: Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA, Zijlstra JM, Markova J, Meissner J, Feuring-Buske M, Hüttmann A, Dierlamm J, Soekler M, Beck HJ, Willenbacher W, Ludwig WD, Pabst T, Topp MS, Hitz F, Bentz M, Keller UB, Kühnhardt D, Ostermann H, Schmitz N, Hertenstein B, Aulitzky W, Maschmeyer G, Vieler T, Eich H, Baues C, Stein H, Fuchs M, Kuhnert G, Diehl V, Dietlein M, Engert A. PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2017 Dec 23;390(10114):2790-2802. Epub 2017 Oct 20. link to original article PubMed
    2. Update: Kreissl S, Goergen H, Buehnen I, Kobe C, Moccia A, Greil R, Eichenauer DA, Zijlstra JM, Markova J, Meissner J, Feuring-Buske M, Soekler M, Beck HJ, Willenbacher W, Ludwig WD, Pabst T, Topp MS, Hitz F, Bentz M, Keller UB, Kühnhardt D, Ostermann H, Hertenstein B, Aulitzky W, Maschmeyer G, Vieler T, Eich H, Baues C, Stein H, Fuchs M, Diehl V, Dietlein M, Engert A, Borchmann P; German Hodgkin Study Group. PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8(6):e398-e409. link to original article PubMed
  4. GITIL/FIL HD 0607: Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mulé A, Picardi M, Romano A, Cantonetti M, La Nasa G, Trentin L, Bolis S, Rapezzi D, Battistini R, Gottardi D, Gavarotti P, Corradini P, Cimminiello M, Schiavotto C, Parvis G, Zanotti R, Gini G, Ferreri AJM, Viero P, Miglino M, Billio A, Avigdor A, Biggi A, Fallanca F, Ficola U, Gregianin M, Chiaravalloti A, Prosperini G, Bergesio F, Chauvie S, Pavoni C, Gianni AM, Rambaldi A. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018 Feb 10;36(5):454-462. Epub 2018 Jan 23. link to original article contains dosing details in supplement PubMed NCT00795613
    1. Update: Gallamini A, Rossi A, Patti C, Picardi M, Romano A, Cantonetti M, Oppi S, Viviani S, Bolis S, Trentin L, Gini G, Battistini R, Chauvie S, Sorasio R, Pavoni C, Zanotti R, Cimminiello M, Schiavotto C, Viero P, Mulé A, Fallanca F, Ficola U, Tarella C, Guerra L, Rambaldi A. Consolidation Radiotherapy Could Be Safely Omitted in Advanced Hodgkin Lymphoma With Large Nodal Mass in Complete Metabolic Response After ABVD: Final Analysis of the Randomized GITIL/FIL HD0607 Trial. J Clin Oncol. 2020 Nov 20;38(33):3905-3913. Epub 2020 Sep 18. Erratum in: J Clin Oncol. 2021 Jan 1;39(1):96. link to original article PubMed

eBEACOPP (Prednisolone)

eBEACOPP: escalated Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisolone

Regimen

Study Dates of enrollment Evidence
Johnson et al. 2016 (RATHL) 2008-2012 Non-randomized part of phase 3 RCT

Note: unlike most BEACOPP regimens, this one uses prednisolone (not prednisone).

Preceding treatment

  • Induction ABVD x 2, with interim PET-CT showing Deauville score 4 or 5 refractory disease

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Growth factor support with ONE of the following:

21-day cycle for 3 cycles

Subsequent treatment

  • RATHL, second interim PET-CT negative: eBEACOPP continuation x 1 (4 total)

References

  1. RATHL: Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, d'Amore F, Enblad G, Franceschetto A, Fulham M, Luminari S, O'Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016 Jun 23;374(25):2419-29. link to original article link to protocol contains dosing details in supplement link to PMC article PubMed NCT00678327
    1. Update: Luminari S, Fossa A, Trotman J, Molin D, d'Amore F, Enblad G, Berkahn L, Barrington SF, Radford J, Federico M, Kirkwood AA, Johnson PWM. Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial. J Clin Oncol. 2024 Jan 1;42(1):13-18. Epub 2023 Oct 26. link to original article link to PMC article PubMed

BeGEV

BeGEV: Bendamustine, GEmcitabine, Vinorelbine

Regimen

Study Dates of enrollment Evidence
Santoro et al. 2016 (ONC-2010-002) 2011-09 to 2014-03 Phase 2

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Growth factor support
  • PJP prophylaxis and antiemetics in accordance with institutional guidelines

21-day cycle for 4 cycles

Subsequent treatment

References

  1. ONC-2010-002: Santoro A, Mazza R, Pulsoni A, Re A, Bonfichi M, Zilioli VR, Salvi F, Merli F, Anastasia A, Luminari S, Annechini G, Gotti M, Peli A, Liberati AM, Di Renzo N, Castagna L, Giordano L, Carlo-Stella C. Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: final results of a multicenter phase II study. J Clin Oncol. 2016 Sep 20;34(27):3293-9. Epub 2016 Jul 5. link to original article contains dosing details in manuscript PubMed NCT01884441

Bendamustine monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Moskowitz et al. 2013 (MSK 08-041) 2008-2010 Phase 2 ORR: 53%

Chemotherapy

Supportive therapy

28-day cycle for up to 6 cycles

References

  1. MSK 08-041: Moskowitz AJ, Hamlin PA Jr, Perales MA, Gerecitano J, Horwitz SM, Matasar MJ, Noy A, Palomba ML, Portlock CS, Straus DJ, Graustein T, Zelenetz AD, Moskowitz CH. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013 Feb 1;31(4):456-60. Epub 2012 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00705250

Bendamustine & Brentuximab vedotin

BVB: Brentuximab Vedotin & Bendamustine

Regimen

Study Dates of enrollment Evidence Efficacy
LaCasce et al. 2018 (SGN35-016) 2013-2014 Phase 1/2 ORR: 92.5%

Prior treatment criteria

  • Standard upfront chemotherapy

Chemotherapy

Antibody-drug conjugate therapy

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. SGN35-016: LaCasce AS, Bociek RG, Sawas A, Caimi P, Agura E, Matous J, Ansell SM, Crosswell HE, Islas-Ohlmayer M, Behler C, Cheung E, Forero-Torres A, Vose J, O'Connor OA, Josephson N, Wang Y, Advani R. Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood. 2018 Jul 5;132(1):40-48. Epub 2018 Apr 27. link to original article contains dosing details in abstract link to PMC article contains dosing details in manuscript PubMed NCT01874054

Brentuximab vedotin monotherapy

Regimen variant #1, q3wk cycle x 4

Study Dates of enrollment Evidence Efficacy
Chen et al. 2015 (CoH 11051) 2011-2014 Phase 2 ORR: 68%

Antibody-drug conjugate therapy

21-day cycle for 4 cycles

Subsequent treatment

  • Auto HSCT consolidation, with choice of regimen left to discretion of treating physician]]


Regimen variant #2, 3 out of 4 weeks

Study Dates of enrollment Evidence Efficacy
Moskowitz et al. 2015 (MSK 11-142) 2012-01-05 to 2013-10-04 Phase 2 PET-negative rate: 27% (95% CI, 13-40)

Antibody-drug conjugate therapy

28-day cycle for 2 cycles

Subsequent treatment

  • MSK 11-142, PET-negative patients (a Deauville score of 1 or 2): Autologous HSCT consolidation with BEAM, CBV, or high dose chemoradiotherapy
  • MSK 11-142, PET-positive patients: Two cycles of augmented ICE intensification prior to transplant

References

  1. Retrospective: Rothe A, Sasse S, Goergen H, Eichenauer DA, Lohri A, Jäger U, Bangard C, Böll B, von Bergwelt Baildon M, Theurich S, Borchmann P, Engert A. Brentuximab vedotin for relapsed or refractory CD30+ hematologic malignancies: the German Hodgkin Study Group experience. Blood. 2012 Aug 16;120(7):1470-2. Epub 2012 Jul 11. link to original article contains dosing details in manuscript PubMed
  2. Retrospective: Gopal AK, Bartlett NL, Forero-Torres A, Younes A, Chen R, Friedberg JW, Matous JV, Shustov AR, Smith SE, Zain J, O'Meara MM, Fanale MA. Brentuximab vedotin in patients aged 60 years or older with relapsed or refractory CD30-positive lymphomas: a retrospective evaluation of safety and efficacy. Leuk Lymphoma. 2014 Oct;55(10):2328-34. Epub 2014 Feb 24. link to original article PubMed
  3. Case series: Illidge T, Bouabdallah R, Chen R, Gopal AK, Moskowitz CH, Ramchandren R, Shustov AR, Tilly H, Trippett TM, Gibb A, Grove LE, Advani R. Allogeneic transplant following brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Leuk Lymphoma. 2015 Mar;56(3):703-10. Epub 2015 Jan 21 link to original article PubMed
  4. MSK 11-142: Moskowitz AJ, Schöder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J, Grewal R, Hamlin PA, Horwitz S, Kobos R, Kumar A, Matasar M, Noy A, Palomba ML, Perales MA, Portlock CS, Sauter C, Shukla N, Steinherz P, Straus D, Trippett T, Younes A, Zelenetz A, Moskowitz CH. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015 Mar;16(3):284-92. Epub 2015 Feb 13. link to original article contains dosing details in abstract PubMed NCT01508312
  5. CoH 11051: Chen R, Palmer JM, Martin P, Tsai N, Kim Y, Chen BT, Popplewell L, Siddiqi T, Thomas SH, Mott M, Sahebi F, Armenian S, Leonard J, Nademanee A, Forman SJ. Results of a multicenter phase II trial of brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2015 Dec;21(12):2136-40. Epub 2015 Jul 26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01393717
    1. Subgroup analysis: Herrera AF, Palmer J, Martin P, Armenian S, Tsai NC, Kennedy N, Sahebi F, Cao T, Budde LE, Mei M, Siddiqi T, Popplewell L, Rosen ST, Kwak LW, Nademanee A, Forman SJ, Chen R. Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol. 2018 Mar 1;29(3):724-730. link to original article link to PMC article PubMed

Brentuximab vedotin & Nivolumab

Regimen

Study Dates of enrollment Evidence Efficacy
Herrera et al. 2017 (SGN35-025) 2015-2016 Phase 1/2 ORR: 82% (95% CI, 70-91)

Note: this is the dosing used for all patients in the trial, per the manuscript. Any subsequent treatment was at the discretion of the treating physician.

Antibody-drug conjugate therapy

Immunotherapy

  • Nivolumab (Opdivo) as follows:
    • Cycle 1: 3 mg/kg IV over 60 minutes once on day 8
    • Cycles 2 to 4: 3 mg/kg IV over 60 minutes once on day 1, given at least 30 minutes after brentuximab vedotin

21-day cycle for up to 4 cycles

References

  1. SGN35-025: Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, LaCasce AS, Ansell SM, Moskowitz CH, Fenton K, Ogden CA, Taft D, Zhang Q, Kato K, Campbell M, Advani RH. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018 Mar 15;131(11):1183-1194. Epub 2017 Dec 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02572167

Camrelizumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Song et al. 2019 (SHR-1210-II-204) 2017 Phase 2 ORR: 76% (95% CI, 65-85)

Immunotherapy

14-day cycles

References

  1. SHR-1210-II-204: Song Y, Wu J, Chen X, Lin T, Cao J, Liu Y, Zhao Y, Jin J, Huang H, Hu J, Luo J, Zhang L, Xue H, Zhang Q, Wang W, Chen C, Feng J, Zhu J. A Single-Arm, Multicenter, Phase II Study of Camrelizumab in Relapsed or Refractory Classical Hodgkin Lymphoma. Clin Cancer Res. 2019 Dec 15;25(24):7363-7369. Epub 2019 Aug 16. link to original article contains dosing details in abstract PubMed NCT03155425

DexaBEAM

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

Regimen variant #1, 2 cycles with standard-dose etoposide

Study Dates of enrollment Evidence
Pfreundschuh et al. 1994 1988-01 to 1990-12 Phase 2

Glucocorticoid therapy

Chemotherapy

Supportive therapy

  • G-CSF starting on day 8, continued until WBC count recovery or the last day of stem-cell harvesting

28-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 2 cycles with higher-dose etoposide

Study Dates of enrollment Evidence
Schmitz et al. 2002 (GHSG HD-R1) 1993-1997 Non-randomized part of RCT

Note: the dose of etoposide was reduced per a mid-protocol amendment.

Glucocorticoid therapy

Chemotherapy

Supportive therapy

  • G-CSF starting on day 8, continued until WBC count recovery or the last day of stem-cell harvesting

2 cycles (length not specified)

Subsequent treatment


Regimen variant #3, 4 cycles total with higher-dose etoposide

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schmitz et al. 2002 (GHSG HD-R1) 1993-1997 Randomized (C) BEAM, then autologous HSCT Seems to have inferior FFTF

Preceding treatment

Glucocorticoid therapy

Chemotherapy

Supportive therapy

  • G-CSF starting on day 8, continued until WBC count recovery or the last day of stem-cell harvesting

2 cycles (length not specified) for a total of 4 cycles

References

  1. Pfreundschuh MG, Rueffer U, Lathan B, Schmitz N, Brosteanu O, Hasenclever D, Haas R, Kirchner H, Koch P, Kuse R, Loeffler M, Diehl V; GHSG. Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group. J Clin Oncol. 1994 Mar;12(3):580-6. link to original article contains dosing details in manuscript PubMed
  2. GHSG HD-R1: Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Müller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V; German Hodgkin's Lymphoma Study Group; Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002 Jun 15;359(9323):2065-71. link to original article contains dosing details in manuscript PubMed

DHAP

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

Regimen

Study Dates of enrollment Evidence
Velasquez et al. 1988 1984-1986 Phase 2
Josting et al. 2010 (GHSG HD-R2) 2000-2006 Non-randomized part of phase 3 RCT
Sureda et al. 2011 (HDR-ALLO) NR Phase 2

Glucocorticoid therapy

Chemotherapy

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 70 years old or younger: 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
    • Older than 70 years old: 1000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 2000 mg/m2)
  • Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1

Supportive therapy

  • Normal saline with mannitol 50 g/L given at 250 mL/H x 36 hours, starting 6 hours prior to cisplatin infusion was started

21- to 28-day cycles; cycle length depends on degree of myelosuppression

Subsequent treatment

Dose and schedule modifications

  • Aside from the table below (from Velasquez et al. 1988), there were no specific cutoff criteria about dose modifications or delays of treatment.
Dose modifications
Event Cytarabine (Ara-C) Cisplatin (Platinol)
ANC less than 200/μL 1000 mg/m2 x 2 doses 100 mg/m2
Platelets less than 20 x 109/L 1000 mg/m2 x 2 doses 100 mg/m2
Sepsis associated with neutropenia 500 mg/m2 x 1 dose 100 mg/m2
Cr 1.5 to 2.0 - 75 mg/m2
Cr 2.1-3.0 - 50 mg/m2

References

  1. Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, Barlogie B. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan;71(1):117-22. link to original article contains dosing details in abstract PubMed
  2. GHSG HD-R2: Josting A, Müller H, Borchmann P, Baars JW, Metzner B, Döhner H, Aurer I, Smardova L, Fischer T, Niederwieser D, Schäfer-Eckart K, Schmitz N, Sureda A, Glossmann J, Diehl V, DeJong D, Hansmann ML, Raemaekers J, Engert A. Dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma. J Clin Oncol. 2010 Dec 1;28(34):5074-80. Epub 2010 Oct 25. link to original article contains dosing details in abstract PubMed NCT00025636
  3. HDR-ALLO: Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcárcel D, Besalduch J, Duarte R, León A, Pascual MJ, García-Noblejas A, López Corral L, Xicoy B, Sierra J, Schmitz N; GEL/TAMO. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma: results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012 Feb;97(2):310-7. Epub 2011 Oct 11. link to original article contains dosing details in abstract link to PMC article PubMed EudraCT 02-0036

DHAP - time intensified

DHAP - time intensified: Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence
Josting et al. 2002 NR Phase 2

Note: This was used as a salvage regimen for relapsed/refractory Hodgkin Lymphoma in patients who were planned for high-dose chemotherapy (HDCT) and autologous hematopoietic cell transplantation. Median time between cycle 1 and 2 was 16 days. The paper did not definitively specify what criteria needed to be fulfilled before cycle 2 was given.

Eligibility criteria

  • WBC count more than 3.5 x 109/L
  • Hgb greater than or equal to 8 g/dL
  • Platelets greater than or equal to 100 x 109/L

Glucocorticoid therapy

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

  • Hydration at 250 mL/H started 2 to 6 hours prior to cisplatin infusion was started
  • Prednisolone acetate 1% eyedrops 1 drop to both eyes three times per day, beginning 12 hours prior to cytarabine and continued for 2 days after administration complete
  • Ondansetron (Zofran) 8 mg IV once per day on days 1 & 2
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, beginning 24 hours after last dose of cytarabine and continued until ANC greater than 2500/μL for 3 days

Variable number of days between cycles depending on count recovery for 2 cycles

References

  1. Josting A, Rudolph C, Reiser M, Mapara M, Sieber M, Kirchner HH, Dörken B, Hossfeld DK, Diehl V, Engert A; Participating Centers. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease. Ann Oncol. 2002 Oct;13(10):1628-35. link to original article contains dosing details in abstract PubMed

ESHAP

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

Regimen

Study Dates of enrollment Evidence
Aparicio et al. 1999 1990-1997 Phase 2

Note: the authors state that they used the protocol defined by Velasquez et al. 1994. However, there are some differences in the text describing methylprednisolone dosing from that in the original article. Below are the doses reported in the original article, with the addition of G-CSF as specified in Aparicio et al. 1999.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21- to 28-day cycle for 3 cycles; see below

Subsequent treatment

  • Aparicio et al. 1999, transplant-eligible patients with responsive disease: CBV with auto HSCT consolidation
  • Aparicio et al. 1999, transplant-ineligible patients with responsive disease: ESHAP continuation x 3 (6 cycles total)

References

  1. Aparicio J, Segura A, Garcerá S, Oltra A, Santaballa A, Yuste A, Pastor M. ESHAP is an active regimen for relapsing Hodgkin's disease. Ann Oncol. 1999 May;10(5):593-5. link to original article contains dosing details in manuscript PubMed

Everolimus monotherapy

Regimen

Study Dates of enrollment Evidence
Johnston et al. 2010 2005-08 to 2007-05 Phase 2

Targeted therapy

Supportive therapy

  • "Patients could receive white blood cell growth factors if neutropenia developed. Erythropoietin treatment for anemia was permitted."

28-day cycles

References

  1. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, Micallef IN, Porrata LF, Ansell SM, Reeder CB, Roy V, Witzig TE. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010 May;85(5):320-4. link to original article contains dosing details in manuscript link to PMC article PubMed

GCD

GCD: Gemcitabine, Carboplatin, Dexamethasone

Regimen

Study Dates of enrollment Evidence
Gopal et al. 2010 (PSOC 2003) 2003-12 to 2008-04 Phase 2

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Growth factor support and antibiotic prophylaxis used is at the discretion of the treating physician.

21-day cycle for up to 4 cycles; if counts not adequate, the next cycle can be delayed for up to 3 weeks until counts are adequate for treatment

Dose and schedule modifications

  • Gemcitabine (Gemzar):
    • If on day 8, platelets are 50 to 100 x 109/L or ANC 500 to 1000/μL: reduce dose by 25% for that dose only.
    • If on day 8, platelets are less than 50 x 109/L or ANC less than 500/μL: No day 8 dose given.
    • Subsequent cycles would be given at full dose if patients had platelets greater than or equal to 50 x 109/L or ANC greater than or equal to 1000/μL.

References

  1. PSOC 2003: Gopal AK, Press OW, Shustov AR, Petersdorf SH, Gooley TA, Daniels JT, Garrison MA, Gjerset GF, Lonergan M, Murphy AE, Smith JC, Pagel JM. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010 Aug;51(8):1523-9. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00072514

GCD-R

GCD-R: Gemcitabine, Carboplatin, Dexamethasone, Rituximab

Regimen

Study Dates of enrollment Evidence
Gopal et al. 2010 (PSOC 2003) 2003-12 to 2008-04 Phase 2

Biomarker eligibility criteria

  • CD20+ disease

Chemotherapy

Glucocorticoid therapy

Targeted therapy

Supportive therapy

  • Growth factor support and antibiotic prophylaxis used is at the discretion of the treating physician.

21-day cycle for up to 4 cycles; if counts not adequate, the next cycle can be delayed for up to 3 weeks until counts are adequate for treatment

Dose and schedule modifications

  • Gemcitabine (Gemzar):
    • If on day 8, platelets are 50 to 100 x 109/L or ANC 500 to 1000/μL: reduce dose by 25% for that dose only.
    • If on day 8, platelets are less than 50 x 109/L or ANC less than 500/μL: No day 8 dose given.
    • Subsequent cycles would be given at full dose if patients had platelets greater than or equal to 50 x 109/L or ANC greater than or equal to 1000/μL.

References

  1. PSOC 2003: Gopal AK, Press OW, Shustov AR, Petersdorf SH, Gooley TA, Daniels JT, Garrison MA, Gjerset GF, Lonergan M, Murphy AE, Smith JC, Pagel JM. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010 Aug;51(8):1523-9. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00072514

Gemcitabine monotherapy

Regimen

Study Dates of enrollment Evidence
Santoro et al. 2000 NR Phase 2

Chemotherapy

  • Gemcitabine (Gemzar) as follows:
    • Cycle 1: 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • Subsequent cycles (if no hematologic or nonhematologic toxicities): 1500 mg/m2 IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

  1. Santoro A, Bredenfeld H, Devizzi L, Tesch H, Bonfante V, Viviani S, Fiedler F, Parra HS, Benoehr C, Pacini M, Bonadonna G, Diehl V. Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin Oncol. 2000 Jul;18(13):2615-9. link to original article contains dosing details in manuscript PubMed

Gemcitabine & Rituximab

Regimen

Study Dates of enrollment Evidence
Oki et al. 2007 2002-03 to 2005-08 Phase 2

Prior treatment criteria

  • At least 2 prior chemotherapy regimens

Targeted therapy

Chemotherapy

21-day cycle for up to 6 cycles

Dose and schedule modifications

  • Gemcitabine (Gemzar):
    • Dose level 0: 1250 mg/m2
    • Dose level -1: 1000 mg/m2
    • Dose level -2: 750 mg/m2
    • If ANC less than or equal to 1000/μL on day 1 of the following cycle, delay until count recovery
    • If ANC remains less than or equal to 1000/μL for one week or longer, reduce dose by one level
    • If platelets less than or equal to 50 x 109/L on day 1 of the following cycle, delay until count recovery AND reduce dose by one level

References

  1. Oki Y, Pro B, Fayad LE, Romaguera J, Samaniego F, Hagemeister F, Neelapu S, McLaughlin P, Goy A, Younes A. Phase 2 study of gemcitabine in combination with rituximab in patients with recurrent or refractory Hodgkin lymphoma. Cancer. 2008 Feb 15;112(4):831-6. link to original article contains dosing details in manuscript PubMed

GVD

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

Regimen variant #1, transplant-naive

Study Dates of enrollment Evidence
Bartlett et al. 2007 (CALGB 59804) 2000-2003 Phase 1/2

Note: this corresponds to dose level 1 used in the dose-finding portion of the protocol; see paper for further details.

Chemotherapy

Supportive therapy

  • See dose modifications, below

21-day cycle for 2 to 6 cycles

Subsequent treatment

  • CALGB 59804, SD or better: Autologous HSCT consolidation (details not specified)

Dose and schedule modifications

  • If on day 8, platelets are 50 to 100 x 109/L or ANC 500 to 1000/μL: reduce gemcitabine dose by 25% for that dose only.
  • If on day 8, platelets are less than 50 x 109/L or ANC less than 500/μL: No day 8 gemcitabine dose given.
  • Subsequent cycles would be given at full dose if patients had platelets greater than or equal to 50 x 109/L or ANC greater than or equal to 1000/μL.
  • If counts were not adequate, the next cycle can be delayed for up to 3 weeks until counts are adequate for treatment.
  • If febrile neutropenia occurs: Decrease treatment by one dose level.
  • If febrile neutropenia occurs on dose level -1: treating physician can choose to either:
    • Use filgrastim or sargramostim
    • Reduce dose of gemcitabine and vinorelbine by 25% for all subsequent cycles.
  • If febrile neutropenia reoccurred despite dose reduction patient were discontinued from this protocol.


Regimen variant #2, post-transplant

Study Dates of enrollment Evidence
Bartlett et al. 2007 (CALGB 59804) 2000-2003 Phase 1/2

Note: this corresponds to dose level -1 used in the dose-finding portion of the protocol; see paper for further details.

Chemotherapy

Supportive therapy

  • See dose modifications, below

21-day cycle for 2 to 6 cycles

Dose and schedule modifications

  • If on day 8, platelets are 50 to 100 x 109/L or ANC 500 to 1000/μL: reduce gemcitabine dose by 25% for that dose only.
  • If on day 8, platelets are less than 50 x 109/L or ANC less than 500/μL: No day 8 gemcitabine dose given.
  • Subsequent cycles would be given at full dose if patients had platelets greater than or equal to 50 x 109/L or ANC greater than or equal to 1000/μL.
  • If counts were not adequate, the next cycle can be delayed for up to 3 weeks until counts are adequate for treatment.
  • If febrile neutropenia occurs: Decrease treatment by one dose level.
  • If febrile neutropenia occurs on dose level -1: treating physician can choose to either:
    • Use filgrastim or sargramostim
    • Reduce dose of gemcitabine and vinorelbine by 25% for all subsequent cycles.
  • If febrile neutropenia reoccurred despite dose reduction patient were discontinued from this protocol.

References

  1. CALGB 59804: Bartlett NL, Niedzwiecki D, Johnson JL, Friedberg JW, Johnson KB, van Besien K, Zelenetz AD, Cheson BD, Canellos GP; Cancer and Leukemia Group B. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol. 2007 Jun;18(6):1071-9. Epub 2007 Apr 10. link to original article contains dosing details in abstract PubMed

GVP

GVP: Gemcitabine, Vinorelbine, Prednisolone

Regimen

Study Dates of enrollment Evidence
Naqi et al. 2013 NR Phase 2

Chemotherapy

Glucocorticoid therapy

28-day cycle for 4 cycles

References

  1. Naqi N, Ahmad S, Shah I, Khattak J. A multicentre phase-II feasibility study evaluating gemcitabine/vinorelbine / prednisolone combination chemotherapy in relapsed / refractory Hodgkin's lymphoma. J Coll Physicians Surg Pak. 2013 Jun;23(6):397-400. link to original article contains dosing details in manuscript PubMed

ICE

ICE: Ifosfamide, Carboplatin, Etoposide

Regimen variant #1

Study Dates of enrollment Evidence
Moskowitz et al. 2001 1994-10 to 1998-02 Phase 2

Chemotherapy

Supportive therapy

14-day cycle for 2 cycles

Dose and schedule modifications

  • No dose reductions--treatment is delayed until ANC is greater than 1000/μL and platelets greater than 50 x 109/L


Regimen variant #2, "Augmented ICE"

Study Dates of enrollment Evidence
Moskowitz et al. 2015 (MSK 11-142) 2012-01-05 to 2013-10-04 Phase 2

Preceding treatment

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 5000 mg/m2/day IV continuous infusion over 48 hours, started on day 1, admixed with ifosfamide (total dose per cycle: 10,000 mg/m2)

2 cycles (length not specified)

Subsequent treatment

  • Autologous HSCT consolidation was "considered" after 2 cycles; criteria not listed in the abstract

References

  1. Moskowitz CH, Nimer SD, Zelenetz AD, Trippett T, Hedrick EE, Filippa DA, Louie D, Gonzales M, Walits J, Coady-Lyons N, Qin J, Frank R, Bertino JR, Goy A, Noy A, O'Brien JP, Straus D, Portlock CS, Yahalom J. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001 Feb 1;97(3):616-23. link to original article contains dosing details in abstract PubMed
  2. MSK 11-142: Moskowitz AJ, Schöder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J, Grewal R, Hamlin PA, Horwitz S, Kobos R, Kumar A, Matasar M, Noy A, Palomba ML, Perales MA, Portlock CS, Sauter C, Shukla N, Steinherz P, Straus D, Trippett T, Younes A, Zelenetz A, Moskowitz CH. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015 Mar;16(3):284-92. Epub 2015 Feb 13. link to original article contains dosing details in abstract PubMed NCT01508312

Ifosfamide & Vinorelbine

Regimen

Study Evidence
Bonfante et al. 1998 Phase 2

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, admixed with mesna (total dose per cycle: 12,000 mg/m2)
  • Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 5

Glucocorticoid therapy

Supportive therapy

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, admixed with ifosfamide (total dose per cycle: 12,000 mg/m2)
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 14

21-day cycles

References

  1. Bonfante V, Viviani S, Santoro A, Devizzi L, Di Russo A, Zanini M, Soncini F, Soto Parra H, Valagussa P, Bonadonna G. Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease. Br J Haematol. 1998 Nov;103(2):533-5. link to original article contains dosing details in manuscript PubMed

IGEV

IGEV: Ifosfamide, GEmcitabine, Vinorelbine

Regimen

Study Dates of enrollment Evidence
Santoro et al. 2007 1997-2005 Phase 2
Magagnoli et al. 2007 1997-2006 Phase 2
Zinzani et al. 2016 (HD0801) 2008-2013 Non-randomized

Note: Magagnoli et al. 2007 was primarily intended as a mobilization regimen.

Preceding treatment

  • HD0801: ABVD salvage x 2

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • 2L saline solution hyperhydration days 1 to 4
  • Mesna (Mesnex) 2600 mg/m2 IV once per day on days 1 to 4
  • Filgrastim (Neupogen) (dose not specified, but could assume 5 mcg/kg) SC once per day on days 7 to 12, or up to apheresis in the course of hematopoietic cell mobilization

21-day cycle for 4 cycles

Subsequent treatment

References

  1. Santoro A, Magagnoli M, Spina M, Pinotti G, Siracusano L, Michieli M, Nozza A, Sarina B, Morenghi E, Castagna L, Tirelli U, Balzarotti M. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma. Haematologica. 2007 Jan;92(1):35-41. link to original article contains dosing details in manuscript PubMed
  2. Magagnoli M, Spina M, Balzarotti M, Timofeeva I, Isa L, Michieli M, Capizzuto R, Morenghi E, Castagna L, Tirelli U, Santoro A. IGEV regimen and a fixed dose of lenograstim: an effective mobilization regimen in pretreated Hodgkin's lymphoma patients. Bone Marrow Transplant. 2007 Dec;40(11):1019-25. Epub 2007 Oct 1. link to original article contains dosing details in manuscript PubMed
  3. HD0801: Zinzani PL, Broccoli A, Gioia DM, Castagnoli A, Ciccone G, Evangelista A, Santoro A, Ricardi U, Bonfichi M, Brusamolino E, Rossi G, Anastasia A, Zaja F, Vitolo U, Pavone V, Pulsoni A, Rigacci L, Gaidano G, Stelitano C, Salvi F, Rusconi C, Tani M, Freilone R, Pregno P, Borsatti E, Sacchetti GM, Argnani L, Levis A. Interim positron emission tomography response-adapted therapy in advanced-stage Hodgkin lymphoma: final results of the phase II part of the HD0801 study. J Clin Oncol. 2016 Apr 20;34(12):1376-85. Epub 2016 Feb 16. link to original article refers to Santoro et al. 2007 PubMed NCT00784537

Lenalidomide monotherapy

Regimen

Study Dates of enrollment Evidence
Fehniger et al. 2011 (Wash U 07-0233) 2007-2009 Phase 2

Targeted therapy

Supportive therapy

28-day cycles

References

  1. Wash U 07-0233: Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA, Fenske TS, Hurd DD, Goy A, Schneider SE, Keppel CR, Wagner-Johnston ND, Carson KR, Bartlett NL. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011 Nov 10;118(19):5119-25. Epub 2011 Sep 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00540007

MINE

MINE: Mesna, Ifosfamide, Novantrone (Mitoxantrone), Etoposide

Regimen

Study Dates of enrollment Evidence
Rodriguez et al. 1995a NR Phase 2

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 1333 mg/m2 IV over 60 minutes once per day on days 1 to 3, admixed with ifosfamide, then 500 mg PO 4 hours after each IV dose of ifosfamide once per day on days 1 to 3

21- to 28-day cycle for up to 6 cycles

References

  1. Rodriguez MA, Cabanillas FC, Hagemeister FB, McLaughlin P, Romaguera JE, Swan F, Velasquez W. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol. 1995 Jul;6(6):609-11. link to original article contains dosing details in abstract PubMed

Mini-BEAM

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

Regimen variant #1, 1 day of treatment/cycle

Study Dates of enrollment Evidence
Fernández-Jiménez et al. 1999 1992-02 to 1998-06 Phase 2

Chemotherapy

28-day cycle for 2 to 3 cycles


Regimen variant #2, 6 days of treatment/cycle

Study Dates of enrollment Evidence
Colwill et al. 1995 NR Phase 2

Chemotherapy

Supportive therapy

  • If febrile neutropenia occurred during previous cycle: Ciprofloxacin (Cipro) 500 mg PO once per day
  • Patients were transfused to keep Hb greater than or equal to 8 g/dL, platelets greater than or equal to 20 x 109/L
  • There was no routine use of G-CSF or GM-CSF

4- to 6-week cycles, depending on hematologic recovery Patients eligible for autologous hematopoietic cell transplant received no more than 2 cycles; otherwise total # of cycles not reported

References

  1. Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993 Apr 24;341(8852):1051-4. link to original article PubMed
  2. Colwill R, Crump M, Couture F, Danish R, Stewart AK, Sutton DM, Scott JG, Sutcliffe SB, Brandwein JM, Keating A. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease before intensive therapy and autologous bone marrow transplantation. J Clin Oncol. 1995 Feb;13(2):396-402. link to original article contains dosing details in abstract PubMed
  3. Fernández-Jiménez MC, Canales MA, Ojeda E, de Bustos JG, Aguado MJ, Hernández-Navarro F. Salvage chemotherapy with mini-BEAM for relapsed or refractory Hodgkin's disease prior to autologous peripheral blood stem cell transplantation. Haematologica. 1999 Nov;84(11):1007-11. link to original article contains dosing details in manuscript PubMed
    1. Update: Martín A, Fernández-Jiménez MC, Caballero MD, Canales MA, Pérez-Simón JA, García de Bustos J, Vázquez L, Hernández-Navarro F, San Miguel JF. Long-term follow-up in patients treated with Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease. Br J Haematol. 2001 Apr;113(1):161-71. link to original article contains dosing details in abstract PubMed

Nivolumab monotherapy

Regimen variant #1, every 2 weeks

Study Dates of enrollment Evidence Efficacy
Younes et al. 2016 (CheckMate 205) 2014-2015 Phase 2 (RT) ORR: 69% (95% CI, 63-75)1

1Reported efficacy is based on the 2018 update.

Immunotherapy

14-day cycles


Regimen variant #2, with lead-in

Study Dates of enrollment Evidence Efficacy
Ansell et al. 2014 (CheckMate 039) 2012-NR Phase 1, >20 pts (RT) ORR: 87%

Immunotherapy

21-day course, then 14-day cycle for up to 51 cycles (2 years)

References

  1. CheckMate 039: Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015 Jan 22;372(4):311-9. Epub 2014 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01592370
  2. CheckMate 205: Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, Armand P, Fanale M, Ratanatharathorn V, Kuruvilla J, Cohen JB, Collins G, Savage KJ, Trneny M, Kato K, Farsaci B, Parker SM, Rodig S, Roemer MG, Ligon AH, Engert A. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016 Sep;17(9):1283-94. Epub 2016 Jul 20. link to original article contains dosing details in abstract link to PMC article PubMed NCT02181738
    1. Update: Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA, Kato K, Sumbul A, Farsaci B, Ansell SM. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol. 2018 May 10;36(14):1428-1439. Epub 2018 Mar 27. Erratum in: J Clin Oncol. 2018 Sep 10;36(26):2748. link to original article link to PMC article PubMed

O-ESHAP

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

Regimen

Study Dates of enrollment Evidence
Martínez et al. 2016 (O-ESHAP-LH-2009) 2010-2013 Phase 2

Note: the ofatumumab dosing is described in the abstract but the ESHAP is not. The ESHAP doses here are from the protocol defined by Velasquez et al. 1994.

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

Glucocorticoid therapy

Number of cycles not specified

References

  1. O-ESHAP-LH-2009: Martínez C, Díaz-López A, Rodriguez-Calvillo M, García-Sanz R, Terol MJ, Pérez-Ceballos E, Jiménez MJ, Cantalapiedra A, Domingo-Domenech E, Rodriguez MJ, Sampol A, Espeso M, López FJ, Briones J, García JF, Sureda A; GELTAMO. Phase II trial of ofatumumab plus ESHAP (O-ESHAP) as salvage treatment for patients with relapsed or refractory classical Hodgkin lymphoma after first-line chemotherapy. Br J Haematol. 2016 Sep;174(6):859-67. Epub 2016 May 17. link to original article contains dosing details in abstract PubMed NCT01195766

Penpulimab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (AK105-201) 2018-NR Phase 2

Immunotherapy

14-day cycles

References

  1. AK105-201: contains dosing details on CT.gov NCT03722147

Rituximab monotherapy

Regimen

Study Dates of enrollment Evidence
Younes et al. 2003 NR Pilot, >20 pts

Note: All reported patients had nodular sclerosis histology.

Prior treatment criteria

  • Minimum of 2 prior systemic regimens

Targeted therapy

7-day cycle for 6 cycles

References

  1. Younes A, Romaguera J, Hagemeister F, McLaughlin P, Rodriguez MA, Fiumara P, Goy A, Jeha S, Manning JT Jr, Jones D, Abruzzo LV, Medeiros LJ. A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer. 2003 Jul 15;98(2):310-4. link to original article contains dosing details in manuscript PubMed

Sintilimab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Shi et al. 2019 (ORIENT-1) 2017 Phase 2 ORR: 80% (95% CI, 71-88)

Immunotherapy

14-day cycles

References

  1. ORIENT-1: Shi Y, Su H, Song Y, Jiang W, Sun X, Qian W, Zhang W, Gao Y, Jin Z, Zhou J, Jin C, Zou L, Qiu L, Li W, Yang J, Hou M, Zeng S, Zhang Q, Hu J, Zhou H, Xiong Y, Liu P. Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2019 Jan;6(1):e12-e19. link to original article contains dosing details in abstract PubMed NCT03114683

Tislelizumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Song et al. 2019 (RATIONALE-203) 2017-04-21 to 2017-11-22 Phase 2 ORR: 87% (95% CI, 77-94)1

1Reported efficacy is based on the 2022 update.

Immunotherapy

21-day cycles

References

  1. RATIONALE-203: Song Y, Gao Q, Zhang H, Fan L, Zhou J, Zou D, Li W, Yang H, Liu T, Wang Q, Lv F, Guo H, Yang L, Elstrom R, Huang J, Novotny W, Wei V, Zhu J. Treatment of relapsed or refractory classical Hodgkin lymphoma with the anti-PD-1, tislelizumab: results of a phase 2, single-arm, multicenter study. Leukemia. 2020 Feb;34(2):533-542. Epub 2019 Sep 13. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03209973
    1. Update: Song Y, Gao Q, Zhang H, Fan L, Zhou J, Zou D, Li W, Yang H, Liu T, Wang Q, Lv F, Guo H, Zhao X, Wang D, Zhang P, Wang Y, Wang L, Liu T, Zhang Y, Shen Z, Huang J, Zhu J. Tislelizumab for Relapsed/Refractory Classical Hodgkin Lymphoma: 3-Year Follow-up and Correlative Biomarker Analysis. Clin Cancer Res. 2022 Mar 15;28(6):1147-1156. link to original article link to PMC article PubMed

Vinblastine monotherapy

Regimen

Study Evidence
Little et al. 1998 Retrospective

Note: This was a retrospective study; we are not aware of a prospective trial of vinblastine monotherapy in this setting.

Chemotherapy

7- to 14-day cycles

References

  1. Retrospective: Little R, Wittes RE, Longo DL, Wilson WH. Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant. J Clin Oncol. 1998 Feb;16(2):584-8. link to original article contains dosing details in abstract PubMed

Vinorelbine monotherapy

Regimen

Study Dates of enrollment Evidence
Devizzi et al. 1994 1992-03 to 1993-03 Phase 2

Note: Complete responders received 6 additional doses past CR; others continued until progression or a maximum of 24 doses.

Chemotherapy

Up to 24-week course (see note)

References

  1. Devizzi L, Santoro A, Bonfante V, Viviani S, Balzarini L, Valagussa P, Bonadonna G. Vinorelbine: an active drug for the management of patients with heavily pretreated Hodgkin's disease. Ann Oncol. 1994 Nov;5(9):817-20. link to original article contains dosing details in manuscript PubMed

Zimberelimab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Lin et al. 2021 (YH-S001-04) 2018-2019 Phase 2 ORR: 91% (95% CI, 82-96)

Immunotherapy

14-day cycle for up to 52 cycles (2 years)

References

  1. YH-S001-04: Lin N, Zhang M, Bai H, Liu H, Cui J, Ke X, Zhang H, Liu L, Yan D, Jiang Y, Zang A, Qi J, Wang L, Liu Z, Xu B, Zhang Y, Zhang Z, Zhao X, Hu C, Yang S, Zhou H, Shi J, Shao Z, Xiang Y, Zhu J, Song Y, Zhu J. Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study. Eur J Cancer. 2022 Mar;164:117-126. Epub 2021 Aug 27. link to original article contains dosing details in manuscript PubMed NCT03655483

Consolidation after salvage therapy

BEAM, then allo HSCT

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

Regimen

Study Dates of enrollment Evidence
Sobol et al. 2013 2000-05 to 2012-04 Phase 2

Chemotherapy

Immunotherapy

GVHD prophylaxis

One course

References

  1. Sobol U, Rodriguez T, Smith S, Go A, Vimr R, Parthasarathy M, Guo R, Stiff P. Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease. Leuk Lymphoma. 2014 Jun;55(6):1281-7. Epub 2013 Oct 3. link to original article contains dosing details in manuscript PubMed

BEAM, then auto HSCT

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Linch et al. 1993 NR Phase 3 (C) Mini-BEAM Superior PFS
Schmitz et al. 2002 (GHSG HD-R1) 1993-1997 Randomized (E-esc) DexaBEAM Seems to have superior FFTF

Linch et al. 1993 was closed early due to patient request for the HSCT arm; dosing details are not available in the abstract.

Preceding treatment

Chemotherapy

Supportive therapy

One course

References

  1. Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993 Apr 24;341(8852):1051-4. link to original article PubMed
  2. GHSG HD-R1: Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Müller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V; German Hodgkin's Lymphoma Study Group; Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002 Jun 15;359(9323):2065-71. link to original article contains dosing details in manuscript PubMed

BeEAM, then auto HSCT

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

Regimen

Study Dates of enrollment Evidence
Visani et al. 2011 2008-08 to 2010-06 Phase 1/2, fewer than 20 pts in this subgroup

Chemotherapy

Supportive therapy

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 variant #1, 1500/300/250, all BSA-based

Study Evidence
Zinzani et al. 2003 Retrospective

Chemotherapy

Supportive therapy

One course


Regimen variant #2, 1800/600/400

Study Evidence
Reece et al. 1994 Phase 2, fewer than 20 pts

Chemotherapy

Supportive therapy

One course

References

  1. Reece DE, Connors JM, Spinelli JJ, Barnett MJ, Fairey RN, Klingemann HG, Nantel SH, O'Reilly S, Shepherd JD, Sutherland HJ, Voss N, Chan KW, Phillips GL. Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy. Blood. 1994 Mar 1;83(5):1193-9. link to original article contains dosing details in manuscript PubMed
  2. Retrospective: Zinzani PL, Tani M, Gabriele A, Gherlinzoni F, de Vivo A, Ricci P, Bandini G, Lemoli RM, Motta MR, Rizzi S, Giudice V, Zompatori M, Stefoni V, Alinari L, Musuraca G, Bassi S, Conte R, Pileri S, Tura S, Baccarani M. High-dose therapy with autologous transplantation for Hodgkin's disease: the Bologna experience. Haematologica. 2003 May;88(5):522-8. link to original article contains dosing details in manuscript PubMed

CBV-Mx, then auto HSCT

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

Regimen

Study Evidence
Morschhauser et al. 2008 (GELA/SFGM H96) Non-randomized

Chemotherapy

Supportive therapy

One course

References

  1. GELA/SFGM H96: Morschhauser F, Brice P, Fermé C, Diviné M, Salles G, Bouabdallah R, Sebban C, Voillat L, Casasnovas O, Stamatoullas A, Bouabdallah K, André M, Jais JP, Cazals-Hatem D, Gisselbrecht C; GELA; SFGM. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol. 2008 Dec 20;26(36):5980-7. Epub 2008 Nov 17. link to original article contains dosing details in manuscript PubMed
    1. Update: Sibon D, Morschhauser F, Resche-Rigon M, Ghez D, Dupuis J, Marçais A, Deau-Fischer B, Bouabdallah R, Sebban C, Salles G, Brice P. Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group. Haematologica. 2016 Apr;101(4):474-81. Epub 2015 Dec 31. link to original article link to PMC article PubMed

FEAM, then auto HSCT

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

Regimen

Study Dates of enrollment Evidence
Musso et al. 2009 2007-2008 Phase 2
Musso et al. 2015 2007-2012 Non-randomized

Chemotherapy

Supportive therapy

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 contains dosing details in abstract PubMed
  2. Musso M, Messina G, Di Renzo N, Di Carlo P, Vitolo U, Scalone R, Marcacci G, Scalzulli PR, Moscato T, Matera R, Crescimanno A, Santarone S, Orciuolo E, Merenda A, Pavone V, Pastore D, Donnarumma D, Carella AM, Ciochetto C, Cascavilla N, Mele A, Lanza F, Di Nicola M, Bonizzoni E, Pinto A. Improved outcome of patients with relapsed/refractory Hodgkin lymphoma with a new fotemustine-based high-dose chemotherapy regimen. Br J Haematol. 2016 Jan;172(1):111-21. Epub 2015 Oct 12. link to original article link to PMC article contains dosing details in abstract PubMed

Fludarabine & Melphalan, then allo HSCT

Flu-Mel: Fludarabine & Melphalan

Regimen variant #1, 132/140

Study Dates of enrollment Evidence
Anderlini et al. 2008 2001-2005 Phase 2

Note: the regimen as reported here is what the authors were using towards the end of the study period; see paper for details.

Preceding treatment

  • Salvage treatment (not specified), with chemosensitive or stable disease

Chemotherapy

Immunotherapy

GVHD prophylaxis

  • ATG (type not specified) by the following donor-based criteria:
    • Matched unrelated donor: 2 mg/kg IV once per day on days -4 to -2
  • Tacrolimus (Prograf) IV starting on day -2, dosed to achieve serum levels 4 to 12 ng/mL and switched to PO as soon as possible. Continued for at least 6 months and then "tapered off" (instructions not given).
  • Methotrexate (MTX) 5 mg/m2 IV once per day on days +1, +3, +6 (extra dose on day +11 for MUD recipients)

One course


Regimen variant #2, 150/140

Study Dates of enrollment Evidence
Alvarez et al. 2006 1999-06 to 2004-01 Prospective
Sureda et al. 2011 (HDR-ALLO) NR Phase 2

Preceding treatment

  • Alvarez et al. 2006: Not specified
  • HDR-ALLO: DHAP salvage x 2

Chemotherapy

Immunotherapy

GVHD prophylaxis

  • Recipients of stem cells from matched unrelated donors received:
  • Cyclosporine starting on day -2 at 1.5 mg/kg IV twice per day
    • If no acute GVHD of grade 2 or more, cyclosporine A is tapered down by 10% per week starting on day +90 with planned discontinuation by day +150 (Alvarez et al. 2006) or +180 (HDR-ALLO).
  • Methotrexate (MTX) 10 mg/m2 IV once per day on days +1, +3, +6, +11

One course


Regimen variant #3, 150/40, with alemtuzumab

Study Evidence
Peggs et al. 2005 Non-randomized

Chemotherapy

Immunotherapy

GVHD prophylaxis

One course

References

  1. Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, Craddock C, Pettengell R, Dogan A, Thomson KJ, Morris EC, Hale G, Waldmann H, Goldstone AH, Linch DC, Mackinnon S. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005 Jun 4-10;365(9475):1934-41. link to original article contains dosing details in manuscript PubMed
  2. Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin lymphoma: results of a Spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006 Feb;12(2):172-83. link to original article contains dosing details in abstract PubMed
  3. Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated MD Anderson Cancer Center experience. Haematologica. 2008 Feb;93(2):257-64. Epub 2008 Jan 26. link to original article contains dosing details in manuscript link to PMC article PubMed
  4. HDR-ALLO: Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcárcel D, Besalduch J, Duarte R, León A, Pascual MJ, García-Noblejas A, López Corral L, Xicoy B, Sierra J, Schmitz N; GEL/TAMO; EBMT. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma: results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012 Feb;97(2):310-7. Epub 2011 Oct 11. link to original article contains dosing details in manuscript link to PMC article PubMed EudraCT 02-0036

Radiation therapy

RT: Radiation Therapy

Regimen variant #1, involved node RT (INRT)

Study Dates of enrollment Evidence
Raemaekers et al. 2014 (EORTC/LYSA/FIL H10) 2006-2009 Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Radiotherapy


Regimen variant #2, involved field RT (IFRT)

Study Dates of enrollment Evidence
Radford et al. 2015 (UK NCRI RAPID) 2003-2010 Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Radiotherapy

References

  1. EORTC/LYSA/FIL H10: Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article contains dosing details in abstract PubMed NCT00433433
    1. Update: André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. link to original article PubMed
    2. Update: Federico M, Fortpied C, Stepanishyna Y, Gotti M, van der Maazen R, Cristinelli C, Re A, Plattel W, Lazarovici J, Merli F, Specht L, Schiano de Colella JM, Hutchings M, Versari A, Edeline V, Stamatoulas A, Girinsky T, Ricardi U, Aleman B, Meulemans B, Tonino S, Raemaekers J, André M. Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma. J Clin Oncol. 2024 Jan 1;42(1):19-25. Epub 2023 Nov 15. link to original article link to PMC article PubMed
  2. UK NCRI RAPID: Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O'Doherty M, Barrington S. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015 Apr 23;372(17):1598-607. link to original article contains dosing details in abstract PubMed NCT00943423

Maintenance after salvage therapy

Brentuximab vedotin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moskowitz et al. 2015 (AETHERA) 2010-2012 Phase 3 (E-RT-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 42.9 vs 24.1 mo
(HR 0.57, 95% CI 0.40-0.81)

Treatment begins 30 to 45 days after transplant.

Preceding treatment

Antibody-drug conjugate therapy

21-day cycle for 16 cycles

References

  1. AETHERA: Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Gianni AM, Carella A, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Sievers EL, Chi A, Larsen EK, Hunder NN, Walewski J; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015 May 9;385(9980):1853-62. Epub 2015 Mar 18. Erratum in: Lancet. 2015 Aug 8;386(9993):532. link to original article contains dosing details in manuscript PubMed NCT01100502
    1. HRQoL analysis: Ramsey SD, Nademanee A, Masszi T, Holowiecki J, Abidi M, Chen A, Stiff P, Viviani S, Sweetenham JW, Radford J, Zhu Y, Bonthapally V, Thomas E, Richhariya A, Hunder NN, Walewski J, Moskowitz CH. Quality of life results from a phase 3 study of brentuximab vedotin consolidation following autologous haematopoietic stem cell transplant for persons with Hodgkin lymphoma. Br J Haematol. 2016 Dec;175(5):860-867. Epub 2016 Sep 21. link to original article link to PMC article PubMed
    2. Update: Moskowitz CH, Walewski J, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Viviani S, Bachanova V, Sureda A, McClendon T, Lee C, Lisano J, Sweetenham J. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood. 2018 Dec 20;132(25):2639-2642. Epub 2018 Sep 28. link to original article PubMed

Relapsed or refractory, transplant ineligible or progressed after transplant

Brentuximab vedotin monotherapy

Regimen variant #1, q3wk cycle x 16

Study Dates of enrollment Evidence Efficacy
Younes et al. 2012 (SG035-0003) 2009 Phase 2 (RT) ORR: 75% (95% CI, 65-83)

Antibody-drug conjugate therapy

21-day cycle for up to 16 cycles


Regimen variant #2, q3wk cycle x 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kuruvilla et al. 2021 (KEYNOTE-204) 2016-2018 Phase 3 (C) Pembrolizumab Inferior PFS

Antibody-drug conjugate therapy

21-day cycle for up to 35 cycles (2 years)


Regimen variant #3, q3wk, indefinite

Study Dates of enrollment Evidence Efficacy
Younes et al. 2010 (SG035-0001) 2006-2009 Phase 1
Gopal et al. 2012 (SGN35-006) 2009-NR Phase 2 ORR: 50%

Note: SGN35-006 is a re-treatment trial; all patients were previously exposed to brentuximab vedotin. Patients who had received the 1.2 mg/kg dose on a prior trial also received that dose at re-treatment.

Antibody-drug conjugate therapy

Supportive therapy

  • Rothe et al. 2012: "no premedications were administered"

21-day cycles

References

  1. SG035-0001: Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010 Nov 4;363(19):1812-21. link to original article PubMed NCT00430846
  2. SG035-0003: Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012 Jun 20;30(18):2183-9. Epub 2012 Mar 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00848926
    1. Update: Gopal AK, Chen R, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Connors JM, Engert A, Larsen EK, Chi X, Sievers EL, Younes A. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015 Feb 19;125(8):1236-43. Epub 2014 Dec 22. link to original article link to PMC article PubMed
    2. Update: Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Connors JM, Engert A, Larsen EK, Huebner D, Fong A, Younes A. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016 Sep 22;128(12):1562-6. Epub 2016 Jul 18. link to original article link to PMC article PubMed
  3. SGN35-006: Gopal AK, Ramchandren R, O'Connor OA, Berryman RB, Advani RH, Chen R, Smith SE, Cooper M, Rothe A, Matous JV, Grove LE, Zain J. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012 Jul 19;120(3):560-8. Epub 2012 Apr 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00947856
    1. Update: Bartlett NL, Chen R, Fanale MA, Brice P, Gopal A, Smith SE, Advani R, Matous JV, Ramchandren R, Rosenblatt JD, Huebner D, Levine P, Grove L, Forero-Torres A. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014 Mar 19;7:24. link to original article contains dosing details in manuscript link to PMC article PubMed
  4. SGN35-007: Gopal AK, Ramchandren R, O'Connor OA, Berryman RB, Advani RH, Chen R, Smith SE, Cooper M, Rothe A, Matous JV, Grove LE, Zain J. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012 Jul 19;120(3):560-8. Epub 2012 Apr 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01026233
    1. Update: Bartlett NL, Chen R, Fanale MA, Brice P, Gopal A, Smith SE, Advani R, Matous JV, Ramchandren R, Rosenblatt JD, Huebner D, Levine P, Grove L, Forero-Torres A. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014 Mar 19;7:24. link to original article contains dosing details in manuscript link to PMC article PubMed
  5. SGN35-008: Gopal AK, Ramchandren R, O'Connor OA, Berryman RB, Advani RH, Chen R, Smith SE, Cooper M, Rothe A, Matous JV, Grove LE, Zain J. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012 Jul 19;120(3):560-8. Epub 2012 Apr 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01026415
    1. Update: Bartlett NL, Chen R, Fanale MA, Brice P, Gopal A, Smith SE, Advani R, Matous JV, Ramchandren R, Rosenblatt JD, Huebner D, Levine P, Grove L, Forero-Torres A. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014 Mar 19;7:24. link to original article contains dosing details in manuscript link to PMC article PubMed
  6. Retrospective: Rothe A, Sasse S, Goergen H, Eichenauer DA, Lohri A, Jäger U, Bangard C, Böll B, von Bergwelt Baildon M, Theurich S, Borchmann P, Engert A. Brentuximab vedotin for relapsed or refractory CD30+ hematologic malignancies: the German Hodgkin Study Group experience. Blood. 2012 Aug 16;120(7):1470-2. Epub 2012 Jul 11. link to original article contains dosing details in manuscript PubMed
  7. Retrospective: Gopal AK, Bartlett NL, Forero-Torres A, Younes A, Chen R, Friedberg JW, Matous JV, Shustov AR, Smith SE, Zain J, O'Meara MM, Fanale MA. Brentuximab vedotin in patients aged 60 years or older with relapsed or refractory CD30-positive lymphomas: a retrospective evaluation of safety and efficacy. Leuk Lymphoma. 2014 Oct;55(10):2328-34. Epub 2014 Feb 24. link to original article PubMed
  8. KEYNOTE-204: Kuruvilla J, Ramchandren R, Santoro A, Paszkiewicz-Kozik E, Gasiorowski R, Johnson NA, Fogliatto LM, Goncalves I, de Oliveira JSR, Buccheri V, Perini GF, Goldschmidt N, Kriachok I, Dickinson M, Komarnicki M, McDonald A, Ozcan M, Sekiguchi N, Zhu Y, Nahar A, Marinello P, Zinzani PL; KEYNOTE-204 investigators. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2021 Apr;22(4):512-524. Epub 2021 Mar 12. link to original article contains dosing details in manuscript PubMed NCT02684292

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chen et al. 2017 (KEYNOTE-087) 2015-2016 Phase 2 (RT) ORR: 72% (95% CI, 65-78)
Kuruvilla et al. 2021 (KEYNOTE-204) 2016-2018 Phase 3 (E-RT-switch-ooc) Brentuximab vedotin Superior PFS (co-primary endpoint)
Median PFS: 13.2 vs 8.3 mo
(HR 0.65, 95% CI 0.48-0.88)

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-087: Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Zhang Y, Ricart AD, Balakumaran A, Moskowitz CH; KEYNOTE-087 Investigators. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017 Jul 1;35(19):2125-2132. Epub 2017 Apr 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02453594
    1. Update: Chen R, Zinzani PL, Lee HJ, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Lin J, Kim E, Nahar A, Balakumaran A, Moskowitz CH. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood. 2019 Oct 3;134(14):1144-1153. Epub 2019 Aug 13. link to original article link to PMC article PubMed
    2. Update: Armand P, Zinzani PL, Lee HJ, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Herrera AF, Lin J, Kim E, Chakraborty S, Marinello P, Moskowitz CH. Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma. Blood. 2023 Sep 7;142(10):878-886. link to original article PubMed
  2. KEYNOTE-204: Kuruvilla J, Ramchandren R, Santoro A, Paszkiewicz-Kozik E, Gasiorowski R, Johnson NA, Fogliatto LM, Goncalves I, de Oliveira JSR, Buccheri V, Perini GF, Goldschmidt N, Kriachok I, Dickinson M, Komarnicki M, McDonald A, Ozcan M, Sekiguchi N, Zhu Y, Nahar A, Marinello P, Zinzani PL; KEYNOTE-204 investigators. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2021 Apr;22(4):512-524. Epub 2021 Mar 12. link to original article contains dosing details in manuscript PubMed NCT02684292

Prognosis

Advanced Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI)

References

  1. Rodday AM, Parsons SK, Upshaw JN, Friedberg JW, Gallamini A, Hawkes E, Hodgson D, Johnson P, Link BK, Mou E, Savage KJ, Zinzani PL, Maurer M, Evens AM. The Advanced-Stage Hodgkin Lymphoma International Prognostic Index: Development and Validation of a Clinical Prediction Model From the HoLISTIC Consortium. J Clin Oncol. 2023 Apr 10;41(11):2076-2086. Epub 2022 Dec 10. Erratum in: J Clin Oncol. 2024 Jan 11. link to original article link to PMC article PubMed

Response criteria

NCI Sponsored International Working Group Criteria (1999)

Intended for non-Hodgkin lymphoma (NHL) but often referred to in the Hodgkin lymphoma literature.

  1. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999 Apr;17(4):1244. Review. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article PubMed

International Harmonization Project on Lymphoma (2007)

  1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. Epub 2007 Jan 22. link to original article PubMed

Juweid's criteria (2007)

  1. Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A, Wiseman GA, Kostakoglu L, Scheidhauer K, Buck A, Naumann R, Spaepen K, Hicks RJ, Weber WA, Reske SN, Schwaiger M, Schwartz LH, Zijlstra JM, Siegel BA, Cheson BD; Imaging Subcommittee of International Harmonization Project in Lymphoma. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007 Feb 10;25(5):571-8. Epub 2007 Jan 22. link to original article PubMed

Deauville criteria (2009)

Note: the definition of "positive" versus "negative" varies and should be confirmed within individual protocols. This is a 5-point scale.

  • 1: no residual FDG uptake above the background level
  • 2: residual FDG uptake less than or equal to the mediastinum
  • 3: residual FDG uptake greater than the mediastinum but not greater than the liver
  • 4: residual FDG uptake moderately increased compared with the liver
  • 5: residual FDG uptake markedly increased compared with the liver or new sites of disease.

References

  1. Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009 Aug;50(8):1257-60. link to original article PubMed
  2. Barrington SF, Qian W, Somer EJ, Franceschetto A, Bagni B, Brun E, Almquist H, Loft A, Højgaard L, Federico M, Gallamini A, Smith P, Johnson P, Radford J, O'Doherty MJ. Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging. 2010 Oct;37(10):1824-33. Epub 2010 May 27. link to original article PubMed
  3. Biggi A, Gallamini A, Chauvie S, Hutchings M, Kostakoglu L, Gregianin M, Meignan M, Malkowski B, Hofman MS, Barrington SF. International validation study for interim PET in ABVD-treated, advanced-stage Hodgkin lymphoma: interpretation criteria and concordance rate among reviewers. J Nucl Med. 2013 May;54(5):683-90. Epub 2013 Mar 20. link to original article PubMed
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