Indolent lymphoma - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. Is there a regimen missing from this list? Please go to the main iNHL regimen page to find other regimens.

Last updated on 2024-07-23:
1 regimens on this page
1 variants on this page


First-line therapy

COPA

COPA: Cyclophosphamide, Oncovin (Vincristine), Prednisone, Adriamycin (Doxorubicin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Connell et al. 1987 1978-1983 Phase 3 (C) 1. COPA-B
2. CAP-BOP
Did not meet efficacy endpoints
Smalley et al. 1992 (ECOG E6484) 1985-1988 Phase 3 (C) I-COPA Inferior TTTF

Note: this regimen is very similar but distinct from CHOP. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Glucocorticoid therapy

28-day cycle for 8 cycles

References

  1. O'Connell MJ, Harrington DP, Earle JD, Johnson GJ, Glick JH, Carbone PP, Creech RH, Neiman RS, Mann RB, Silverstein MN; ECOG. Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma. J Clin Oncol. 1987 Sep;5(9):1329-39. link to original article PubMed
  2. ECOG E6484: Smalley RV, Andersen JW, Hawkins MJ, Bhide V, O'Connell MJ, Oken MM, Borden EC. Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med. 1992 Nov 5;327(19):1336-41. link to original article dosing details in manuscript have been reviewed by our editors PubMed


CVP

CVP: Cyclophosphamide, Vincristine, Prednisone
COP: Cyclophosphamide, Oncovin (Vincristine), Prednisone
VCP: Vincristine, Cyclophosphamide, Prednisone

Regimen variant #1, 750/1.4/40

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hagenbeek et al. 2006 1993-1997 Phase 3 (C) Fludarabine Did not meet primary endpoint of PFS48 Less toxic
Marcus et al. 2004 (M39021) 2000-2002 Phase 3 (C) R-CVP Inferior TTP Similar toxicity

Chemotherapy

Glucocorticoid therapy

21-day cycle for up to 8 cycles


Regimen variant #2, 1000/1.4/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hochster et al. 2009 (ECOG E1496) Not reported Phase 3 (C) FC Not reported

Note: the FC arm was closed prematurely and comparisons between CVP and FC were not conducted.

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 to 8 cycles

Subsequent treatment


Regimen variant #3, 2000/1.4/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Unterhalt et al. 1996 1989-04 to 1996-01 Phase 3 (C) PmM Seems to have inferior EFS

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. Unterhalt M, Herrmann R, Tiemann M, Parwaresch R, Stein H, Trümper L, Nahler M, Reuss-Borst M, Tirier C, Neubauer A, Freund M, Kreuser ED, Dietzfelbinger H, Bodenstein H, Engert A, Stauder R, Eimermacher H, Landys K, Hiddemann W; German Low-Grade Lymphoma Study Group. Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. Leukemia. 1996 May;10(5):836-43. PubMed
    1. Update: Hiddemann W, Unterhalt M, Herrmann R, Wöltjen HH, Kreuser ED, Trümper L, Reuss-Borst M, Terhardt-Kasten E, Busch M, Neubauer A, Kaiser U, Hanrath RD, Middeke H, Helm G, Freund M, Stein H, Tiemann M, Parwaresch R. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998 May;16(5):1922-30. link to original article PubMed
  2. M39021: Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. Epub 2004 Oct 19.link to original article dosing details in abstract have been reviewed by our editors PubMed
    1. Update: Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, Offner FC, Gomez-Codina J, Belch A, Cunningham D, Wassner-Fritsch E, Stein G. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008 Oct 1;26(28):4579-86. Epub 2008 Jul 28. link to original article PubMed
  3. Hagenbeek A, Eghbali H, Monfardini S, Vitolo U, Hoskin PJ, de Wolf-Peeters C, MacLennan K, Staab-Renner E, Kalmus J, Schott A, Teodorovic I, Negrouk A, van Glabbeke M, Marcus R. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma. J Clin Oncol. 2006 Apr 1;24(10):1590-6. link to original article dosing details in abstract have been reviewed by our editors PubMed
  4. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003204
    1. Update: Barta SK, Li H, Hochster HS, Hong F, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Colocci N, Bengtson EM, Horning SJ, Kahl BS. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer. 2016 Oct;122(19):2996-3004. Epub 2016 Jun 28. link to original article link to PMC article PubMed


Fludarabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zinzani et al. 2000 1995-1998 Phase 3 (C) Fludarabine & Idarubicin Superior CR rate1

1The superiority of this arm was only observed in the FL subgroup; overall, there was no statistically significant difference between arms.
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

28-day cycle for 6 cycles

References

  1. Zinzani PL, Magagnoli M, Moretti L, De Renzo A, Battista R, Zaccaria A, Guardigni L, Mazza P, Marra R, Ronconi F, Lauta VM, Bendandi M, Gherlinzoni F, Gentilini P, Ciccone F, Cellini C, Stefoni V, Ricciuti F, Gobbi M, Tura S. Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma. J Clin Oncol. 2000 Feb;18(4):773-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Cyclophosphamide & Fludarabine (FC)

FC: Fludarabine & Cyclophosphamide
CF: Cyclophosphamide & Fludarabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hochster et al. 2009 (ECOG E1496) Not reported Phase 3 (E-switch-ic) CVP Not reported

Note: investigation into this regimen was halted due to excess mortality.

Chemotherapy

28-day cycle for up to 8 cycles

Subsequent treatment

References

  1. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003204


FND

FND: Fludarabine, Novantrone (Mitoxantrone), Dexamethasone

Regimen

Study Dates of enrollment Evidence
McLaughlin et al. 1996 1992-01 to 1993-12 Phase 2

Chemotherapy

Glucocorticoid therapy

28-day cycle for up to 8 cycles

References

  1. McLaughlin P, Hagemeister FB, Romaguera JE, Sarris AH, Pate O, Younes A, Swan F, Keating M, Cabanillas F. Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol. 1996 Apr;14(4):1262-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed


ProMACE-MOPP

ProMACE-MOPP: Prolix (Prednisone), Methotrexate, Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide, Mustargen (Mechlorethamine), Oncovin (Vincristine), Procarbazine, Prednisone

References

  1. Young RC, Longo DL, Glatstein E, Ihde DC, Jaffe ES, DeVita VT Jr. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol. 1988 Apr;25(2 Suppl 2):11-6. does not contain dosing details in abstract PubMed


Relapsed or refractory

Fludarabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Klasa et al. 2002 1993-1996 Phase 3 (E-switch-ic) CVP Seems to have superior PFS

Chemotherapy

28-day cycles

References

  1. Klasa RJ, Meyer RM, Shustik C, Sawka CA, Smith A, Guévin R, Maksymiuk A, Rubinger M, Samosh M, Laplante S, Grenier JF. Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol. 2002 Dec 15;20(24):4649-54. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Fludarabine & Rituximab (FR)

FR: Fludarabine & Rituximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003) 2003-2010 Phase 3 (C) BR Inferior PFS

Chemotherapy

Targeted therapy

28-day cycle for up to 6 cycles

References

  1. StiL NHL 2-2003: Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01456351


FMP

FMP: Fludarabine, Mitoxantrone, Prednisone

Regimen

Study Dates of enrollment Evidence
Zinzani et al. 1995a 1993-11 to 1994-06 Phase 2

Chemotherapy

Glucocorticoid therapy

21-day cycle for up to 6 cycles

References

  1. Zinzani PL, Bendandi M, Tura S. FMP regimen (fludarabine, mitoxantrone, prednisone) as therapy in recurrent low-grade non-Hodgkin's lymphoma. Eur J Haematol. 1995 Oct;55(4):262-6. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Idelalisib monotherapy

Regimen

Study Dates of enrollment Evidence
Gopal et al. 2014 (DELTA) 2011-2012 Phase 2 (RT)

Targeted therapy

Continued indefinitely

References

  1. DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01282424
    1. Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). Blood 2014 124:1708. link to abstract


Interferon alfa monotherapy

Regimen

Study Dates of enrollment Evidence
Foon et al. 1984 Not reported Phase 2

Immunotherapy

References

  1. Foon KA, Sherwin SA, Abrams PG, Longo DL, Fer MF, Stevenson HC, Ochs JJ, Bottino GC, Schoenberger CS, Zeffren J, Jaffe ES, Oldham RK. Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon. N Engl J Med. 1984 Nov 1;311(18):1148-52. link to original article PubMed


131Iodine-Tositumomab monotherapy

Regimen

Study Dates of enrollment Evidence
Kaminski et al. 1993 Not reported Non-randomized, fewer than 20 pts
Press et al. 1995 Not reported Phase 2
Kaminski et al. 2001 (RIT-II-004) 1996-1998 Phase 2 (RT)
Horning et al. 2004 (CP-97-012) 1998-1999 Phase 2 (RT)
Olney et al. 2014 (SB-393229/032) 2004-2007 Phase 2

Note: Kiminski et al. 1993 and Press et al. 1995 are included here for historic context but had different treatment details.

Radioconjugate therapy, dosimetric step

  • On Day 0, infusions of:
  • Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
  • Day 6 or 7: Third scan of whole body dosimetry & redistribution

Radioconjugate therapy, therapeutic step

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

Supportive therapy, therapeutic step

References

  1. Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, Burgess JM, Petry NA, Butchko GM, Glenn SD, Wahl RL. Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med. 1993 Aug 12;329(7):459-65. link to original article PubMed
  2. Press OW, Eary JF, Appelbaum FR, Martin PJ, Nelp WB, Glenn S, Fisher DR, Porter B, Matthews DC, Gooley T, Bernstein ID. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet. 1995 Aug 5;346(8971):336-40. link to original article PubMed
  3. RIT-II-004: Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2001 Oct 1;19(19):3918-28. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  4. CP-97-012: Horning SJ, Younes A, Jain V, Kroll S, Lucas J, Podoloff D, Goris M. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol. 2005 Feb 1;23(4):712-9. Epub 2004 Dec 21. link to original article PubMed
  5. Meta-analysis: Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, Vose JM, Leonard JP, Kroll S, Goldsmith SJ, Coleman M. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol. 2005 Oct 20;23(30):7565-73. Epub 2005 Sep 26. link to original article PubMed
  6. SB-393229/032: Olney HJ, Freeman MA, Stewart DA, Mangel JE, White DJ, Elia-Pacitti JO. Prolonged progression-free survival and preserved quality of life in the Canadian prospective study of tositumomab and iodine(131)-tositumomab for previously treated, rituximab-exposed, indolent non-Hodgkin lymphoma. Leuk Lymphoma. 2014 Dec;55(12):2754-60. Epub 2014 Apr 3. link to original article PubMed NCT00240565


Ofatumumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Maloney et al. 2020 (HOMER) 2010-2016 Phase 3 (E-switch-ic) Rituximab Did not meet primary endpoint of PFS

Note: there was no MTD determined in Hx-CD20-001.

Targeted therapy

  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
    • Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22

Supportive therapy

28-day cycle for 2 cycles

References

  1. HOMER: Maloney DG, Ogura M, Fukuhara N, Davis J, Lasher J, Izquierdo M, Banerjee H, Tobinai K. A phase 3 randomized study (HOMER) of ofatumumab vs rituximab in iNHL relapsed after rituximab-containing therapy. Blood Adv. 2020 Aug 25;4(16):3886-3893. link to original article link to PMC article PubMed NCT01200589


Umbralisib monotherapy

Regimen

Study Dates of enrollment Evidence
Fowler et al. 2021 (UNITY-NHL) 2017-2018 Phase 2b (RT)

Targeted therapy

28-day cycles

References

  1. UNITY-NHL: Fowler NH, Samaniego F, Jurczak W, Ghosh N, Derenzini E, Reeves JA, Knopińska-Posłuszny W, Cheah CY, Phillips T, Lech-Maranda E, Cheson BD, Caimi PF, Grosicki S, Leslie LA, Chavez JC, Fonseca G, Babu S, Hodson DJ, Shao SH, Burke JM, Sharman JP, Law JY, Pagel JM, Miskin HP, Sportelli P, O'Connor OA, Weiss MS, Zinzani PL. Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2021 May 20;39(15):1609-1618. Epub 2021 Mar 8. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02793583