Follicular lymphoma

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78 regimens on this page
111 variants on this page

Contents


Guidelines

ESMO

Current

Older

NCCN

Untreated, randomized data

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Rummel et al. 2013 (StiL NHL1) Phase III R-CHOP Superior PFS
Flinn et al. 2014 (BRIGHT) Phase III R-CHOP
R-CVP
Superior PFS (*)

Efficacy in BRIGHT is based on the 2017 update. Patients in BRIGHT were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy.

Chemotherapy

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

Supportive medications

  • Antiemetics, antipyretics, and antibiotics according to local standard of care
  • Prophylactic use of G-CSF allowed according ASCO guidelines (2006)

28-day cycle for up to 6 cycles (StiL NHL1) or 8 cycles (BRIGHT)

References

  1. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article contains verified protocol PubMed
    1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
    2. Update: Abstract: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, and Wolfram Brugger. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. Journal of Clinical Oncology 2017 35:15_suppl, 7501-7501 link to abstract
  2. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article contains verified protocol PubMed
    1. Update: Abstract: Ian Flinn, Richard van der Jagt, Julie E. Chang, Peter Wood, Tim E. Hawkins, David MacDonald, Judith Trotman, David Simpson, Kathryn S. Kolibaba, Samar Issa, Doreen M. Hallman, Ling Chen, and John M. Burke. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study. Journal of Clinical Oncology 2017 35:15_suppl, 7500-7500 link to abstract

Chlorambucil (Leukeran)

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Regimen

Study Evidence Comparator Efficacy
Ardeshna et al. 2003 Phase III Observation Seems not superior

This is the comparator arm to the "watch and wait" strategy, and is not commonly used.

Chemotherapy

Indefinitely

References

  1. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. link to original article contains verified protocol PubMed

Cyclophosphamide (Cytoxan)

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Regimen

Study Evidence Comparator Efficacy
Peterson et al. 2003 (CALGB 7951) Phase III CHOP-B Seems not superior

Chemotherapy

  • Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day
    • Dose modifications according to WBC and platelet count as listed in Table 1 of Peterson et al. 2003

Treatment continued in responders for 2 years beyond maximal response

References

  1. Peterson BA, Petroni GR, Frizzera G, Barcos M, Bloomfield CD, Nissen NI, Hurd DD, Henderson ES, Sartiano GP, Johnson JL, Holland JF, Gottlieb AJ. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003 Jan 1;21(1):5-15. link to original article contains verified protocol PubMed

Lenalidomide & Rituximab

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Regimen

Study Evidence Comparator Efficacy
Kimby et al. 2014 (SAKK 35/10) Randomized Phase II Rituximab Seems to have superior CR/CRu rate

Chemotherapy

  • Lenalidomide (Revlimid) 15 mg PO once per day starting 14 days prior to first rituximab infusion and continuing until 14 days past last rituximab infusion
  • Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 1 to 4, 12 to 15 (8 doses total)

One course

References

  1. Abstract: Eva Kimby, Giovanni Martinelli, Bjorn Ostenstad, Ulrich JM Mey, Daniel Rauch, Björn E Wahlin, MD, PhD, Felicitas Hitz, MD, Micaela Hernberg, Ann-Sofie Johansson, Peter de Nully Brown, Hans Hagberg, Andrés J.M. Ferreri1, Andreas Lohri, Urban Novak, Thilo Zander, Hanne Bersvendsen, Mario Bargetzi, Walter Mingrone, Fatime Krasniqi, Stephan Dirnhofer, Hanne Hawle, MD, Simona Berardi, Steffi Demmel, Stephanie Rondeau and Emanuele Zucca, MD. Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10. ASH Annual Meeting 2014 Abstract 799 link to abstract

Observation

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Regimen

Study Evidence Comparator Efficacy
Horning, Rosenberg 1984 Non-randomized
Young et al. 1988 Phase III ProMACE-MOPP -> TNI
Brice et al. 1997 Phase III Interferon alfa
Prednimustine
Seems not superior
Ardeshna et al. 2003 Phase III Chlorambucil Seems not superior
Ardeshna et al. 2014 Phase III Rituximab induction Inferior TTNT
Rituximab induction -> Rituximab maintenance Inferior TTNT

Also known as "watchful waiting".

References

  1. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med. 1984 Dec 6;311(23):1471-5. link to original article PubMed
  2. 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. PubMed
  3. Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, Straetmans N, Tilly H, Tabah I, Solal-Céligny P. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 1997 Mar;15(3):1110-7. link to original article PubMed
  4. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. link to original article PubMed
  5. Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, Warden J, Stevens L, Pocock CF, Miall F, Cunningham D, Davies J, Jack A, Stephens R, Walewski J, Ferhanoglu B, Bradstock K, Linch DC. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014 Apr;15(4):424-35. Epub 2014 Mar 4. link to original article PubMed

R-CHOP

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

Regimen #1

Study Evidence Comparator Efficacy
Flinn et al. 2014 (BRIGHT) Phase III BR Inconclusive whether non-inferior

Patients were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

Regimen #2

Study Evidence Comparator Efficacy
Salles et al. 2010 (PRIMA) Non-randomized portion of RCT
Federico et al. 2013 (FOLL05) Phase III R-CVP Seems to have superior PFS
R-FM Seems not superior

In PRIMA, initial therapy was investigator's choice. In FOLL05, PFS was superior to R-CVP but equivalent to R-FM; risk/benefit ratio was better than R-FM.

Chemotherapy, R-CHOP portion

21-day cycle for 6 cycles, followed by:

Chemotherapy, rituximab extension

21-day cycle for 2 cycles

In PRIMA, responders (PR or CR) were randomized to maintenance rituximab versus no further treatment.

Regimen #3

Study Evidence Comparator Efficacy
Czuczman et al. 1999 Phase II
Press et al. 2013 (SWOG S0016) Phase III CHOP -> 131Iodine-Tositumomab Seems not superior

In SWOG S0016, this regimen was intended for patients greater than 18 years with untreated bulky stage II or stage III-IV FL (all grades) expressing CD20.

Chemotherapy

21-day cycle for 6 cycles

Regimen #4

Study Evidence Comparator Efficacy
Watanabe et al. 2011 (JCOG 0203) Phase III R-CHOP-14 Seems not superior

This regimen was intended for patients with previously untreated stage III to IV indolent B-cell NHL, including FL grade 3B.

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

Regimen #5

Study Evidence Comparator Efficacy Toxicity
Hiddemann et al. 2005 Phase III CHOP Seems to have superior OS Increased toxicity

Chemotherapy

21-day cycle for 6 to 8 cycles

Regimen #6, CHOP -> R

Study Evidence Comparator Efficacy
Zinzani et al. 2004 Phase III FMR Inferior CR rate

Note: this regimen was for all patients with PR after the CHOP portion, and for patients in CR with detectable bcl-2/IgH fusion by PCR after the CHOP portion.

Chemotherapy, CHOP portion

21-day cycle for 6 cycles, followed by:

Chemotherapy, rituximab portion

4-week course

References

  1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article contains protocol PubMed
    1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed
  2. Rambaldi A, Lazzari M, Manzoni C, Carlotti E, Arcaini L, Baccarani M, Barbui T, Bernasconi C, Dastoli G, Fuga G, Gamba E, Gargantini L, Gattei V, Lauria F, Lazzarino M, Mandelli F, Morra E, Pulsoni A, Ribersani M, Rossi-Ferrini PL, Rupolo M, Tura S, Zagonel V, Zaja F, Zinzani P, Reato G, Foa R. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood. 2002 Feb 1;99(3):856-62. link to original article PubMed
  3. Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. link to original article contains verified protocol PubMed
  4. Hainsworth JD, Litchy S, Morrissey LH, Andrews MB, Grimaldi M, McCarty M, Greco FA. Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the minnie pearl cancer research network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. Epub 2005 Jan 4. link to original article contains verified protocol PubMed
  5. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, Reiser M, Metzner B, Harder H, Hegewisch-Becker S, Fischer T, Kropff M, Reis HE, Freund M, Wörmann B, Fuchs R, Planker M, Schimke J, Eimermacher H, Trümper L, Aldaoud A, Parwaresch R, Unterhalt M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005 Dec 1;106(12):3725-32. Epub 2005 Aug 25. link to original article contains protocol PubMed
  6. Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A, Pulsoni A, Musso M, Liberati AM, Olivieri A, Gallamini A, Pogliani E, Rota Scalabrini D, Callea V, Di Raimondo F, Pavone V, Tucci A, Cortelazzo S, Levis A, Boccadoro M, Majolino I, Pileri A, Gianni AM, Passera R, Corradini P, Tarella C; Gruppo Italiano Trapianto di Midollo Osseo (GITMO); Intergruppo Italiano Linfomi (IIL). Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood. 2008 Apr 15;111(8):4004-13. Epub 2008 Jan 31. link to original article PubMed
  7. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed
    1. Abstract: Update: Gilles Andre Salles, MD, PhD, John Francis Seymour, MBBS, FRACP, PhD, Pierre Feugier, MD, PhD, Fritz Offner, MD, Armando Lopez-Guillermo, MD, PhD, David Belada, M.D., Ph.D., Luc Xerri, MD, PhD, Reda Bouabdallah, MD, John Catalano, MBBS FRACP FRCPA, Brice Pauline, MD, Dolores Caballero, MD, PhD, Corinne Haioun, MD, PhD, Lars Moller Pedersen, Alain Delmer, MD, David Simpson, Sirpa Leppa, Pierre Soubeyran, Anton Hagenbeek, MD, PhD, Olivier Casasnovas, MD, Tanin Intragumtornchai, MD, Christophe Ferme, MD, Maria Gomes da Silva, Catherine Sebban, MD, Andrew Lister, Jane A Estell, MBBS, FRCPA, FRACP, Gustavo Milone, Anne Sonet, MD, Bertrand Coiffier, MD, PhD and Herve Tilly, MD. Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy. Blood 2013 122:509. link to abstract
    2. QoL Analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article PubMed
  8. Watanabe T, Tobinai K, Shibata T, Tsukasaki K, Morishima Y, Maseki N, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Takeuchi K, Nawano S, Terauchi T, Hotta T. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol. 2011 Oct 20;29(30):3990-8. Epub 2011 Sep 19. link to original article contains verified protocol PubMed
  9. Press OW, Unger JM, Rimsza LM, Friedberg JW, Leblanc M, Czuczman MS, Kaminski M, Braziel RM, Spier C, Gopal AK, Maloney DG, Cheson BD, Dakhil SR, Miller TP, Fisher RI. Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus 131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016. J Clin Oncol. 2013 Jan 20;31(3):314-20. Epub 2012 Dec 10. link to original article PubMed
  10. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article PubMed
    1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
    2. Update: Abstract: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, and Wolfram Brugger. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. Journal of Clinical Oncology 2017 35:15_suppl, 7501-7501 link to abstract
  11. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Apr 20;31(12):1506-13. Epub 2013 Mar 25. Erratum in: J Clin Oncol. 2014 Apr 1;32(10):1095. Dosage error in article text. link to original article contains verified protocol PubMed
    1. Update: Abstract: Stefano Luminari, Alessandra Dondi, Luigi Marcheselli, Giuseppe Rossi, Carola Boccomini, Annalisa Chiarenza, Luigi Rigacci, Francesco Merli, Giovanni Bertoldero, Alessandro Levis, Andres J. Ferreri, Daniele Vallisa, Maria Christina Cox, Monica Balzarotti, Massimiliano Salati, Massimo Federico. Updated results of the FOLL05 phase III trial from the Fondazione Italiana Linfomi comparing R-CVP, R-CHOP, and R-FM in patients with advanced follicular lymphoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 8530) link to abstract
  12. Abstract: Armando Lopez-Guillermo, MD, PhD, Miguel A. Canales, MD, PhD, Ivan Dlouhy, Javier Briones, MD, Dolores Caballero, MD, PhD, Juan Manuel Sancho Sr., MD, Santiago Mercadal Vilchez, MD, Jose María Moraleda, MD, María José Terol, MD, PhD, Antonio Salar, MD, Luis Palomera, MD, Santiago Gardella, MD, Isidro Jarque, MD, Secundino Ferrer, Joan Bargay, MD, Andres Lopez, Carlos Panizo, Anna Muntanola, MD, Carlos Montalban, Eulogio Conde, MD, PhD, Miguel Hernandez, MD, Alfons Soler, Julian Marin, MD, Jose García Marco, Guillermo Deben and José Francisco Tomas, MD, PhD. A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization. Blood 2013 122:369. link to abstract
  13. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article contains verified protocol PubMed
    1. Update: Abstract: Ian Flinn, Richard van der Jagt, Julie E. Chang, Peter Wood, Tim E. Hawkins, David MacDonald, Judith Trotman, David Simpson, Kathryn S. Kolibaba, Samar Issa, Doreen M. Hallman, Ling Chen, and John M. Burke. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study. Journal of Clinical Oncology 2017 35:15_suppl, 7500-7500 link to abstract

R-CHVP+I

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R-CHVP+I: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), VP-16 (Etoposide), Prednisolone, Interferon-a2a

Regimen

Study Evidence Comparator Efficacy
Salles et al. 2008 (FL2000) Phase III CHVP+I Superior EFS

Chemotherapy

28-day cycle for 6 cycles

Followed by interferon alfa-2a maintenance.

References

  1. Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi JF, Haioun C, Brice P, Mahé B, Bouabdallah R, Audhuy B, Ferme C, Dartigeas C, Feugier P, Sebban C, Xerri L, Foussard C. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008 Dec 15;112(13):4824-31. Epub 2008 Sep 17. link to original article contains verified protocol PubMed
    1. Update: Bachy E, Houot R, Morschhauser F, Sonet A, Brice P, Belhadj K, Cartron G, Audhuy B, Fermé C, Feugier P, Sebban C, Delwail V, Maisonneuve H, Le Gouill S, Lefort S, Brousse N, Foussard C, Salles G; Groupe d'Etude des Lymphomes de l'Adulte (GELA). Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma. Haematologica. 2013 Jul;98(7):1107-14. Epub 2013 May 3. link to original article PubMed

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen #1

Study Evidence Comparator Efficacy
Flinn et al. 2014 (BRIGHT) Phase III BR Inconclusive whether non-inferior

Patients were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

Regimen #2

Study Evidence Comparator Efficacy Toxicity
Marcus et al. 2005 Phase III CVP Superior TTP Similar toxicity
Salles et al. 2010 (PRIMA) Non-randomized portion of RCT
Federico et al. 2013 (FOLL05) Phase III R-CHOP Seems to have inferior PFS See paper
R-FM Seems to have inferior PFS See paper

Chemotherapy

21-day cycle for up to 8 cycles

In the PRIMA trial, responders (PR or CR) were randomized to maintenance rituximab versus no further treatment.

References

  1. 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. link to original article contains protocol 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
  2. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed
    1. Abstract: Update: Gilles Andre Salles, MD, PhD, John Francis Seymour, MBBS, FRACP, PhD, Pierre Feugier, MD, PhD, Fritz Offner, MD, Armando Lopez-Guillermo, MD, PhD, David Belada, M.D., Ph.D., Luc Xerri, MD, PhD, Reda Bouabdallah, MD, John Catalano, MBBS FRACP FRCPA, Brice Pauline, MD, Dolores Caballero, MD, PhD, Corinne Haioun, MD, PhD, Lars Moller Pedersen, Alain Delmer, MD, David Simpson, Sirpa Leppa, Pierre Soubeyran, Anton Hagenbeek, MD, PhD, Olivier Casasnovas, MD, Tanin Intragumtornchai, MD, Christophe Ferme, MD, Maria Gomes da Silva, Catherine Sebban, MD, Andrew Lister, Jane A Estell, MBBS, FRCPA, FRACP, Gustavo Milone, Anne Sonet, MD, Bertrand Coiffier, MD, PhD and Herve Tilly, MD. Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy. Blood 2013 122:509. link to abstract
    2. QoL Analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article PubMed
  3. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Apr 20;31(12):1506-13. Epub 2013 Mar 25. Erratum in: J Clin Oncol. 2014 Apr 1;32(10):1095. Dosage error in article text. link to original article contains verified protocol PubMed
    1. Update: Abstract: Stefano Luminari, Alessandra Dondi, Luigi Marcheselli, Giuseppe Rossi, Carola Boccomini, Annalisa Chiarenza, Luigi Rigacci, Francesco Merli, Giovanni Bertoldero, Alessandro Levis, Andres J. Ferreri, Daniele Vallisa, Maria Christina Cox, Monica Balzarotti, Massimiliano Salati, Massimo Federico. Updated results of the FOLL05 phase III trial from the Fondazione Italiana Linfomi comparing R-CVP, R-CHOP, and R-FM in patients with advanced follicular lymphoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 8530) link to abstract
  4. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article contains verified protocol PubMed

R-FM; FMR

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R-FM: Rituximab, Fludarabine, Mitoxantrone
FMR: Fludarabine, Mitoxantrone, Rituximab

Regimen

Study Evidence Comparator Efficacy
Federico et al. 2013 (FOLL05) Phase III R-CHOP Seems not superior
R-CVP Seems to have superior PFS

PFS was superior to R-CVP but equivalent to R-CHOP; risk/benefit ratio was worse than R-CHOP.

Chemotherapy, R-FM portion

21-day cycle for 6 cycles, followed by:

Chemotherapy, rituximab extension

21-day cycle for 2 cycles

References

  1. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Apr 20;31(12):1506-13. Epub 2013 Mar 25. Erratum in: J Clin Oncol. 2014 Apr 1;32(10):1095. Dosage error in article text. link to original article contains verified protocol PubMed
    1. Update: Abstract: Stefano Luminari, Alessandra Dondi, Luigi Marcheselli, Giuseppe Rossi, Carola Boccomini, Annalisa Chiarenza, Luigi Rigacci, Francesco Merli, Giovanni Bertoldero, Alessandro Levis, Andres J. Ferreri, Daniele Vallisa, Maria Christina Cox, Monica Balzarotti, Massimiliano Salati, Massimo Federico. Updated results of the FOLL05 phase III trial from the Fondazione Italiana Linfomi comparing R-CVP, R-CHOP, and R-FM in patients with advanced follicular lymphoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 8530) link to abstract

R-FND

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R-FND: Rituximab, Fludarabine, Novantrone (mitoxantrone), Dexamethasone

Regimen

Study Evidence
Vitolo et al. 2013 Non-randomized portion of RCT

Chemotherapy, R-FND portion

Monthly cycle for 4 cycles; non-progressors received:

Chemotherapy, rituximab consolidation

4-week course

Responders were then randomized to rituximab maintenance versus observation.

References

  1. Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F, Tucci A, Botto B, Chiappella A, Chiarenza A, Pinto A, De Renzo A, Zaja F, Castellino C, Bari A, Alvarez De Celis I, Evangelista A, Parvis G, Gamba E, Lobetti-Bodoni C, Ciccone G, Rossi G. Rituximab Maintenance Compared With Observation After Brief First-Line R-FND Chemoimmunotherapy With Rituximab Consolidation in Patients Age Older Than 60 Years With Advanced Follicular Lymphoma: A Phase III Randomized Study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Sep 20;31(27):3351-9. Epub 2013 Aug 19. link to original article contains verified protocol PubMed
  2. Nastoupil LJ, McLaughlin P, Feng L, Neelapu SS, Samaniego F, Hagemeister FB, Ayala A, Romaguera JE, Goy AH, Neal E, Wang M, Fayad L, Fanale MA, Oki Y, Westin JR, Rodriguez MA, Cabanillas F, Fowler NH. High ten-year remission rates following rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) with interferon maintenance in indolent lymphoma: Results of a randomized Study. Br J Haematol. 2017 Apr;177(2):263-270. Epub 2017 Mar 24. link to original article PubMed

R-MCP

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R-MCP: Rituximab, Mitoxantrone, Chlorambucil, Prednisolone

Regimen

Study Evidence Comparator Efficacy
Herold et al. 2007 (OSHO #39) Phase III MCP Superior OS

Chemotherapy

28-day cycle for up to 8 cycles

All patients who achieved a PR or CR were placed on maintenance interferon alfa-2a within 4 to 8 weeks of completion of chemotherapy.

References

  1. Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, Dölken G, Naumann R, Knauf W, Freund M, Rohrberg R, Höffken K, Franke A, Ittel T, Kettner E, Haak U, Mey U, Klinkenstein C, Assmann M, von Grünhagen U; East German Study Group Hematology and Oncology Study. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007 May 20;25(15):1986-92. Epub 2007 Apr 9. link to original article contains verified protocol PubMed
    1. Update: Herold M, Scholz CW, Rothmann F, Hirt C, Lakner V, Naumann R. Long-term follow-up of rituximab plus first-line mitoxantrone, chlorambucil, prednisolone and interferon-alpha as maintenance therapy in follicular lymphoma. J Cancer Res Clin Oncol. 2015 Sep;141(9):1689-95. Epub 2015 Mar 25. link to original article PubMed

Rituximab (Rituxan)

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Regimen #1, 4 doses

Study Evidence Comparator Efficacy
Hainsworth et al. 2000 Phase II
Colombat et al. 2001 Phase II
Hainsworth et al. 2002 Phase II
Ghielmini et al. 2004 (SAKK 35/98) Non-randomized portion of RCT
Ardeshna et al. 2014 Phase III Observation Superior TTNT
Rituximab induction -> Rituximab maintenance Seems not superior
Kahl et al. 2014 (RESORT) Non-randomized portion of RCT
Taverna et al. 2015 (SAKK 35/03) Non-randomized portion of RCT

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per week x 4 weeks; initial infusion rate of 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes, to a maximum rate of 300 mg/H

Supportive medications

4-week course

Patients with response or stable disease in Hainsworth et al. 2002 were treated with maintenance rituximab. Patients with response or stable disease in SAKK 35/98 were randomized to maintenance rituximab versus no further treatment. Patients with PR/CR in RESORT were randomized to indefinite rituximab versus salvage rituximab at time of progression. Patients with PR/CR in SAKK 35/03 were randomized to 9 months of maintenance rituximab versus 5 years of maintenance rituximab.

Regimen #2, 8 doses

Study Evidence Comparator Efficacy
Kimby et al. 2014 (SAKK 35/10) Randomized Phase II Lenalidomide & Rituximab Seems to have inferior CR/CRu rate
Kimby et al. 2015 (NLG) Phase III Rituximab & IFN-α2a Seems not superior

Note: only patients achieving some degree of measurable response in Kimby et al. 2015 proceeded to the 2nd course of rituximab.

Chemotherapy

One course

References

  1. Hainsworth JD, Burris HA 3rd, Morrissey LH, Litchy S, Scullin DC Jr, Bearden JD 3rd, Richards P, Greco FA. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood. 2000 May 15;95(10):3052-6. link to original article PubMed
  2. Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P, Delwail V, Deconinck E, Haïoun C, Foussard C, Sebban C, Stamatoullas A, Milpied N, Boué F, Taillan B, Lederlin P, Najman A, Thièblemont C, Montestruc F, Mathieu-Boué A, Benzohra A, Solal-Céligny P. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001 Jan 1;97(1):101-6. link to original article contains protocol PubMed
    1. Update: Colombat P, Brousse N, Salles G, Morschhauser F, Brice P, Soubeyran P, Delwail V, Deconinck E, Haioun C, Foussard C, Sebban C, Tilly H, Thieblemont C, Bergougnoux L, Lazreg F, Solal-Celigny P. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up. Ann Oncol. 2012 Sep;23(9):2380-5. Epub 2012 Jul 10. link to original article PubMed
  3. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article contains protocol PubMed
  4. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
  5. Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. PubMed
  6. Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, Warden J, Stevens L, Pocock CF, Miall F, Cunningham D, Davies J, Jack A, Stephens R, Walewski J, Ferhanoglu B, Bradstock K, Linch DC. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014 Apr;15(4):424-35. Epub 2014 Mar 4. link to original article contains verified protocol PubMed
  7. Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol. 2014 Oct 1;32(28):3096-102. Epub 2014 Aug 25. link to original article contains verified protocol PubMed
  8. Abstract: Eva Kimby, Giovanni Martinelli, Bjorn Ostenstad, Ulrich JM Mey, Daniel Rauch, Björn E Wahlin, MD, PhD, Felicitas Hitz, MD, Micaela Hernberg, Ann-Sofie Johansson, Peter de Nully Brown, Hans Hagberg, Andrés J.M. Ferreri1, Andreas Lohri, Urban Novak, Thilo Zander, Hanne Bersvendsen, Mario Bargetzi, Walter Mingrone, Fatime Krasniqi, Stephan Dirnhofer, Hanne Hawle, MD, Simona Berardi, Steffi Demmel, Stephanie Rondeau and Emanuele Zucca, MD. Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10. ASH Annual Meeting 2014 Abstract 799 link to abstract
  9. Kimby E, Östenstad B, Brown P, Hagberg H, Erlanson M, Holte H, Linden O, Johansson AS, Ahlgren T, Wader K, Wahlin BE, Delabie J, Sundström C; Nordic Lymphoma Group (NLG). Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. Leuk Lymphoma. 2015;56(9):2598-607. link to original article contains verified protocol PubMed
  10. Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Vanazzi A, Laszlo D, Raats J, Rauch D, Vorobiof DA, Lohri A, Biaggi Rudolf C, Rondeau S, Rusterholz C, Heijnen IA, Zucca E, Ghielmini M. Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03. J Clin Oncol. 2016 Feb 10;34(5):495-500. Epub 2015 Dec 28. link to original article contains verified protocol PubMed

Untreated, non-randomized or retrospective data

Bendamustine & Ofatumumab

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Regimen

Study Evidence
Czuczman et al. 2015 Phase II

The subtypes of indolent lymphoma that this regimen was used for are not specified in the abstract. Given that follicular lymphoma is the most common indolent lymphoma, the regimen is included here.

Chemotherapy

  • Bendamustine 90 mg/m2 IV once per day on days 1 & 2
  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
    • Cycle 2 onwards: 1000 mg IV once on day 1

28-day cycle for 6 cycles

References

  1. Czuczman MS, Kahanic S, Forero A, Davis G, Munteanu M, Van Den Neste E, Offner F, Bron D, Quick D, Fowler N. Results of a phase II study of bendamustine and ofatumumab in untreated indolent B cell non-Hodgkin's lymphoma. Ann Hematol. 2015 Apr;94(4):633-41. Epub 2015 Jan 30. link to original article contains protocol PubMed

Bortezomib & Rituximab

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Regimen

Study Evidence
Evens et al. 2014 Phase II

Chemotherapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 & 3: 375 mg/m2 IV once on day 1

35-day cycle for 3 cycles

Followed by consolidation bortezomib and rituximab.

References

  1. Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-hodgkin lymphoma: a multicentre phase II study. Br J Haematol. 2014 Aug;166(4):514-20. Epub 2014 Apr 25. link to original article contains verified protocol PubMed

BR -> Maintenance Rituximab

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BR: Bendamustine, Rituximab

Regimen

Study Evidence
Rummel et al. 2014 (MAINTAIN) Non-randomized portion of RCT

Chemotherapy, BR portion

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

28-day cycle for up to 6 cycles, followed by:

Chemotherapy, rituximab extension

28-day cycle for 2 cycles

Followed by randomization to rituximab maintenance x 2 years versus rituximab maintenance x 4 years.

References

  1. Abstract: Mathias J. Rummel, MD, Andreas Viardot, Richard Greil, MD, Bernd Hertenstein, MD, Christian Lerchenmüller, MD, Arnold Ganser, Manfred Reeb, MD, Ulrich Kaiser, MD, Christina Balser, MD, Georg Maschmeyer, MD, Heinz Dürk, MD, Georg Schliesser, MD, Tobias Gaska, MD, Jan Dürig, MD, Axel C. Matzdorff, MD, Rudolf Weide, MD, Axel Hinke, PhD, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Jürgen Barth and Wolfram Brugger, MD. Bendamustine Plus Rituximab Followed By Rituximab Maintenance for Patients with Untreated Advanced Follicular Lymphomas. Results from the StiL NHL 7-2008 Trial (MAINTAIN trial) (ClinicalTrials.gov Identifier: NCT00877214). Blood 2014 124:3052 link to abstract

CVP

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CVP: Cyclophosphamide, Vincristine, Prednisone

Synonyms: COP, COP protocol 2, VCP

Structured Concept: C9573 (NCI-T), C0056633 (NCI-MT/UMLS)

Regimen

Study Evidence
Hochster et al. 2009 (ECOG E1496) Non-randomized

Chemotherapy

21-day cycle for 6 to 8 cycles

Patients were then randomized to maintenance rituximab versus observation.

References

  1. 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 contains verified protocol PubMed
    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 PubMed

Fludarabine & Rituximab

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Regimen

Study Evidence
Czuczman et al. 2005 Phase II

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Weeks 2, 6, 10, 14, 18, 22: 25 mg/m2 IV once per day on days 1 to 5
  • Rituximab (Rituxan) as follows:
    • Weeks 1 & 26: 375 mg/m2 IV once per day on days 1 & 4
    • Weeks 6, 14, 22: 375 mg/m2 IV once 72 hours before day 1

26-week course

References

  1. Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, Bernstein ZP, McCarthy P, Alam A, Hernandez-Ilizaliturri F, Skipper M, Brown K, Chanan-Khan A, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-Lopez A, Bernstein SH. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005 Feb 1;23(4):694-704. link to original article contains verified protocol PubMed

FLUMIZ

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FLUMIZ: FLUdarabine, MItoxantrone, Zevalin

Regimen

Study Evidence
Zinzani et al. 2008 (FLUMIZ) Phase II

Chemotherapy

Supportive medications

  • Allopurinol (Zyloprim) 300 mg PO once per day for patients with bulky disease
  • No prophylactic use of G-CSF, but patients with grade 3 or 4 neutropenia or delayed neutropenic fever could be given growth factors for later cycles at physician discretion

28-day cycle for 6 cycles

Patients were restaged 4 to 6 weeks after finishing cycle 6. People with at least a partial response (PR), neutrophil count greater than 1.5 x 109/L, platelet count greater than 100 x 109/L, and less than 25% bone marrow involvement were eligible for consolidation therapy with ibritumomab tiuxetan 6 to 10 weeks after the end of cycle 6:

References

  1. Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol. 2008 Apr;9(4):352-8. Epub 2008 Mar 14. link to original article contains verified protocol PubMed

FMR

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FMR: Fludarabine, Mitoxantrone, Rituximab

Regimen

Study Evidence Comparator Efficacy
Zinzani et al. 2004 Phase III CHOP -> R Superior CR rate

Note: this regimen was for all patients with PR after the FM portion, and for patients in CR with detectable bcl-2/IgH fusion by PCR after the FMR portion.

Chemotherapy, FM portion

21-day cycles x 6 cycles, followed by:

Chemotherapy, rituximab portion

4-week course

References

  1. Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. link to original article contains verified protocol PubMed

FMR-Z

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FMR-Z: Fludarabine, Mitoxantrone, Rituximab, Zevalin

Regimen

Study Evidence
Zinzani et al. 2012 Phase II

Chemotherapy

Supportive medications

  • No prophylactic use of G-CSF, but patients with grade 3 or 4 neutropenia or delayed neutropenic fever could be given growth factors for later cycles at physician discretion

28-day cycle for 4 cycles

Patients were restaged 2 to 3 weeks after finishing cycle 4. People with at least a partial response (PR), neutrophil count greater than 1.5 x 109/L, platelet count greater than 100 x 109/L, and less than 25% bone marrow involvement were eligible for consolidation therapy with ibritumomab tiuxetan, given within 12 weeks (paper does not specify "within 12 weeks" of what).

References

  1. Zinzani PL, Tani M, Pulsoni A, De Renzo A, Stefoni V, Broccoli A, Montini GC, Fina M, Pellegrini C, Gandolfi L, Cavalieri E, Torelli F, Scopinaro F, Argnani L, Quirini F, Derenzini E, Rossi M, Pileri S, Fanti S, Baccarani M. A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by ?°Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. Ann Oncol. 2012 Feb;23(2):415-20. Epub 2011 May 2. link to original article contains verified protocol PubMed

Ibritumomab tiuxetan (Zevalin)

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Regimen #1

Study Evidence
Samaniego et al. 2014 Phase II

Chemoradiotherapy

Regimen #2

Study Evidence
Scholz et al. 2013 Phase II
Ibatici et al. 2013 Phase II

Recruitment in Scholz et al. was limited to patients at least 50 years old due to radiation safety concerns; Ibatici et al. was open to all adult patients greater than 18 years old. Treatment regimen is identical.

Chemoradiotherapy

8 to 9-day course of therapy

References

  1. Scholz CW, Pinto A, Linkesch W, Lindén O, Viardot A, Keller U, Hess G, Lastoria S, Lerch K, Frigeri F, Arcamone M, Stroux A, Frericks B, Pott C, Pezzutto A. 90Yttrium-Ibritumomab-Tiuxetan as First-Line Treatment for Follicular Lymphoma: 30 Months of Follow-Up Data From an International Multicenter Phase II Clinical Trial. J Clin Oncol. 2013 Jan 20;31(3):308-13. Epub 2012 Dec 10. link to original article contains verified protocol PubMed
  2. Ibatici A, Pica GM, Nati S, Vitolo U, Botto B, Ciochetto C, Petrini M, Galimberti S, Ciabatti E, Orciuolo E, Zinzani PL, Cascavilla N, Guolo F, Fraternali Orcioni G, Carella AM. Safety and efficacy of (90) Yttrium-Ibritumomab-Tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study. Br J Haematol. 2014 Mar;164(5):710-6. Epub 2013 Dec 17. link to original article contains verified protocol PubMed
  3. Samaniego F, Berkova Z, Romaguera JE, Fowler N, Fanale MA, Pro B, Shah JJ, McLaughlin P, Sehgal L, Selvaraj V, Braun FK, Mathur R, Feng L, Neelapu SS, Kwak LW. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease. Br J Haematol. 2014 Oct;167(2):207-13. Epub 2014 Jul 8. link to original article contains verified protocol PubMed

Ibritumomab tiuxetan (Zevalin), fractionated

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Regimen

Study Evidence
Illidge et al. 2013 Phase II

This regimen was for patients with less than or equal to 20% bone marrow involvement; others received induction rituximab, first. See paper for details.

Chemoradiotherapy

2 cycles, 8 weeks apart 2nd cycle could be extended to 12 weeks if hematologic recovery was incomplete.

References

  1. Illidge TM, Mayes S, Pettengell R, Bates AT, Bayne M, Radford JA, Ryder WD, Le Gouill S, Jardin F, Tipping J, Zivanovic M, Kraeber-Bodere F, Bardies M, Bodet-Milin C, Malek E, Huglo D, Morschhauser F. Fractionated 90Y-Ibritumomab Tiuxetan Radioimmunotherapy As an Initial Therapy of Follicular Lymphoma: An International Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria. J Clin Oncol. 2014 Jan 20;32(3):212-8. Epub 2013 Dec 2. link to original article contains verified protocol PubMed

Lenalidomide & Rituximab (R2)

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R2: Rituximab & Revlimid (Lenalidomide)

Regimen #1

Study Evidence
Fowler et al. 2014 Phase II

Chemotherapy

28-day cycle for up to 12 cycles

Regimen #2

Study Evidence
Martin et al. 2014 (CALGB 50803) Phase II

Chemotherapy

28-day cycle for 12 cycles

References

  1. Abstract: Peter Martin, Sin-Ho Jung, Jeffrey L. Johnson, Brandy Pitcher, Rebecca L. Elstrom, Nancy Bartlett, Kristie A. Blum, Kristy L. Richards... John Leonard, Bruce D. Cheson. CALGB 50803 (Alliance): A phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. Journal of Clinical Oncology 32, no. 15_suppl (May 2014) 8521-8521. link to abstract
  2. Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article contains protocol PubMed

O-CHOP

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O-CHOP: Ofatumumab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen

Study Evidence
Czuczman et al. 2012 (409 Study) Phase II

Note: both 500 mg and 1000 mg doses of ofatumumab were tested, but since there was no increase in toxicity in patients receiving the 1000 mg dose, the 1000 mg dose was chosen for future ofatumumab trials "to avoid underdosing patients"

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

References

  1. Czuczman MS, Hess G, Gadeberg OV, Pedersen LM, Goldstein N, Gupta I, Jewell RC, Lin TS, Lisby S, Strange C, Windfeld K, Viardot A; 409 Study Investigators. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012 May;157(4):438-45. Epub 2012 Mar 13. link to original article contains verified protocol PubMed

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

Study Evidence
Samaniego et al. 2015 Phase II

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

References

  1. Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. link to original article contains verified protocol PubMed

R-CHOP

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

Regimen

Study Evidence
Hainsworth et al. 2005 Phase II

Chemotherapy, rituximab lead-in

Chemotherapy, R-CHOP portion

21-day cycle for 3 cycles

Chemotherapy, rituximab consolidation

References

  1. Hainsworth JD, Litchy S, Morrissey LH, Andrews MB, Grimaldi M, McCarty M, Greco FA. Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the minnie pearl cancer research network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. Epub 2005 Jan 4. link to original article contains verified protocol PubMed

R-CHOP -> Ibritumomab tiuxetan

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These regimens had pre-planned consolidation with ibritumumab tiuxetan and are thus presented here distinctly from the other R-CHOP regimens. An abstract presented at ASH 2013 from the ZAR2007 trial has preliminary results that this regimen is inferior to R-CHOP followed by rituximab maintenance; detailed results are not yet available and therefore only the reference is provided, here.

Regimen #1

Study Evidence
Hainsworth et al. 2009 Phase II

Chemotherapy, rituximab pre-phase

Four week course, followed by:

Chemotherapy, R-CHOP portion

21-day cycle for 3 cycles

Followed in 4 weeks by ibritumumab tiuxetan consolidation.

Regimen #2

Study Evidence
Jacobs et al. 2008 Phase II

R-CHOP given as per standard ECOG dosing, except that rituximab is given on day 1 of each cycle:

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Followed by ibritumumab tiuxetan consolidation; interval between R-CHOP and Zevalin is not specified in the paper.

References

  1. Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR, DeMonaco N, Joyce J, Osborn JL, Evans TL, Schaefer PM, Luong TM. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res. 2008 Nov 1;14(21):7088-94. link to original article contains verified protocol PubMed
  2. Hainsworth JD, Spigel DR, Markus TM, Shipley D, Thompson D, Rotman R, Dannaher C, Greco FA. Rituximab plus short-duration chemotherapy followed by Yttrium-90 Ibritumomab tiuxetan as first-line treatment for patients with follicular non-Hodgkin lymphoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma. 2009 Jun;9(3):223-8. link to original article contains verified protocol PubMed
  3. Abstract: Armando Lopez-Guillermo, MD, PhD, Miguel A. Canales, MD, PhD, Ivan Dlouhy, Javier Briones, MD, Dolores Caballero, MD, PhD, Juan Manuel Sancho Sr., MD, Santiago Mercadal Vilchez, MD, Jose María Moraleda, MD, María José Terol, MD, PhD, Antonio Salar, MD, Luis Palomera, MD, Santiago Gardella, MD, Isidro Jarque, MD, Secundino Ferrer, Joan Bargay, MD, Andres Lopez, Carlos Panizo, Anna Muntanola, MD, Carlos Montalban, Eulogio Conde, MD, PhD, Miguel Hernandez, MD, Alfons Soler, Julian Marin, MD, Jose García Marco, Guillermo Deben and José Francisco Tomas, MD, PhD. A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization. Blood 2013 122:369. link to abstract

R-CMD

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R-CMD: Rituximab, Cladribine, Mitoxantrone, Dexamethasone

Regimen

Study Evidence
Sakai et al. 2015 Phase II

Note: the dose of dexamethasone in the manuscript text as well as the accompanying table is listed as 8 mg/body. It is unclear to us what this means.

Chemotherapy

21-day cycle for 4 cycles, followed by:

Chemotherapy, rituximab post-phase

28-day cycle for 4 cycles

References

  1. Sakai T, Masaki Y, Otsuki N, Sakamaki I, Kishi S, Miyazono T, Urasaki Y, Murakami J, Satoh T, Nakamura T, Iwao H, Nakajima A, Kawanami T, Miki M, Fujita Y, Tanaka M, Fukushima T, Okazaki T, Ueda T. Prospective clinical study of R-CMD therapy for indolent B cell lymphoma and mantle cell lymphoma from the Hokuriku Hematology Oncology Study Group. Med Oncol. 2015 Sep;32(9):232. link to PMC article contains verified protocol PubMed

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

Study Evidence
Hainsworth et al. 2005 Phase II

Chemotherapy, rituximab pre-phase

One course, followed by:

Chemotherapy, R-CVP portion

21-day cycle for 3 cycles, followed by:

Chemotherapy, rituximab post-phase

References

  1. Hainsworth JD, Litchy S, Morrissey LH, Andrews MB, Grimaldi M, McCarty M, Greco FA. Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the minnie pearl cancer research network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. Epub 2005 Jan 4. link to original article contains verified protocol PubMed

R-FCM

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R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study Evidence
Salles et al. 2010 (PRIMA) Non-randomized portion of RCT

Chemotherapy

28-day cycle for 6 cycles

Responders (PR or CR) were randomized to maintenance rituximab or no further treatment.

References

  1. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed
    1. Abstract: Update: Gilles Andre Salles, MD, PhD, John Francis Seymour, MBBS, FRACP, PhD, Pierre Feugier, MD, PhD, Fritz Offner, MD, Armando Lopez-Guillermo, MD, PhD, David Belada, M.D., Ph.D., Luc Xerri, MD, PhD, Reda Bouabdallah, MD, John Catalano, MBBS FRACP FRCPA, Brice Pauline, MD, Dolores Caballero, MD, PhD, Corinne Haioun, MD, PhD, Lars Moller Pedersen, Alain Delmer, MD, David Simpson, Sirpa Leppa, Pierre Soubeyran, Anton Hagenbeek, MD, PhD, Olivier Casasnovas, MD, Tanin Intragumtornchai, MD, Christophe Ferme, MD, Maria Gomes da Silva, Catherine Sebban, MD, Andrew Lister, Jane A Estell, MBBS, FRCPA, FRACP, Gustavo Milone, Anne Sonet, MD, Bertrand Coiffier, MD, PhD and Herve Tilly, MD. Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy. Blood 2013 122:509. link to abstract
    2. QoL Analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article PubMed

VR-CHOP

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

Regimen

Study Evidence
Cohen et al. 2015 Phase II

The largest group of patients studied in this trial had follicular lymphoma. Note the decreased cap on vincristine.

Chemotherapy

21-day cycle for up to 8 cycles

Patients achieving CR proceeded to rituximab maintenance; others proceeded to bortezomib & rituximab maintenance; further details not available in abstract.

References

  1. Cohen JB, Switchenko JM, Koff JL, Sinha R, Kaufman JL, Khoury HJ, Bumpers N, Colbert A, Hutchison-Rzepka A, Nastoupil LJ, Heffner LT, Langston AA, Lechowicz MJ, Lonial S, Flowers CR. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma. Br J Haematol. 2015 Nov;171(4):539-46. Epub 2015 Aug 7. link to original article contains protocol PubMed

Consolidation and/or maintenance after upfront therapy

Bortezomib & Rituximab

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Regimen

Study Evidence
Evens et al. 2014 Phase II

Treatment preceded by induction bortezomib and rituximab.

Chemotherapy

8 month total consolidation course (4 doses)

References

  1. Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-hodgkin lymphoma: a multicentre phase II study. Br J Haematol. 2014 Aug;166(4):514-20. Epub 2014 Apr 25. link to original article contains verified protocol PubMed
  2. Cohen JB, Switchenko JM, Koff JL, Sinha R, Kaufman JL, Khoury HJ, Bumpers N, Colbert A, Hutchison-Rzepka A, Nastoupil LJ, Heffner LT, Langston AA, Lechowicz MJ, Lonial S, Flowers CR. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma. Br J Haematol. 2015 Nov;171(4):539-46. Epub 2015 Aug 7. link to original article PubMed

Ibritumomab tiuxetan (Zevalin)

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An abstract presented at ASH 2013 from the ZAR2007 trial has preliminary results that R-CHOP followed by Zevalin is inferior to R-CHOP followed by rituximab maintenance; detailed results are not yet available and therefore only the reference is provided, here.

Regimen #1

Study Evidence Comparator Efficacy
Morschhauser et al. 2008 (FIT) Phase III Observation Superior PFS

Consolidation therapy for patients in complete or partial remission after first-line therapy (most received CHOP or CVP; some received "CHOP-like", "rituximab combination", "fludarabine combination", or chlorambucil).

Chemoradiotherapy

8-day course of therapy

Regimen #2

Study Evidence
Zinzani et al. 2012 Phase II

Treatment preceded by FMR-Z.

Chemoradiotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once on day 1 and another single dose on day 7, 8, or 9 (total dose of rituximab is 500 mg/m2)
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) immediately following second dose of rituximab, as follows:
    • Platelet count greater than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes
    • Platelet count of 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes

Regimen #3

Study Evidence
Hainsworth et al. 2009 Phase II

Treatment preceded by R-CHOP x 3.

Chemoradiotherapy

See text for further information about Zevalin eligbility criteria. If patient did not meet criteria within 7 weeks after final R-CHOP, Zevalin was omitted.

Regimen #4

Study Evidence
Zinzani et al. 2008 (FLUMIZ) Phase II

Treatment preceded by FLUMIZ.

Chemoradiotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once on day 1 and another single dose on day 7, 8, or 9 (total dose of rituximab is 500 mg/m2)
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) immediately following second dose of rituximab, as follows:
    • Platelet count greater than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes
    • Platelet count of 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes

Regimen #5

Study Evidence
Jacobs et al. 2008 Phase II

Treatment preceded by R-CHOP x 3.

Chemoradiotherapy

8-day course of therapy, followed in 1 to 2 weeks by:

Chemotherapy

4-week course

Regimen #6

Study Evidence
Provencio et al. 2013 Phase II

Treatment preceded by R-CHOP x 4 or CHOP x 2. Further details are not available in the abstract.

References

  1. Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol. 2008 Apr;9(4):352-8. Epub 2008 Mar 14. link to original article contains verified protocol PubMed
  2. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d'Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. link to original article contains protocol PubMed
    1. Update: Hagenbeek, Anton, Radford, John, Van Hoof, Achiel, Vitolo, Umberto, Rohatiner, Ama Z.S., Salles, Gilles, Soubeyran, Pierre, Tilly, Herve, Delaloye, Angelika Bischof, van Putten, Wim L.J., Morschhauser, Franck. 90Y-Ibritumomab Tiuxetan (Zevalin(R)) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients. ASH Annual Meeting Abstracts 2010 116: 594 link to abstract
    2. Update: Morschhauser F, Radford J, Van Hoof A, Botto B, Rohatiner AZ, Salles G, Soubeyran P, Tilly H, Bischof-Delaloye A, van Putten WL, Kylstra JW, Hagenbeek A. 90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial. J Clin Oncol. 2013 Jun 1;31(16):1977-83. Epub 2013 Apr 1. link to original article contains protocol PubMed
  3. Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR, DeMonaco N, Joyce J, Osborn JL, Evans TL, Schaefer PM, Luong TM. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res. 2008 Nov 1;14(21):7088-94. link to original article contains verified protocol PubMed
  4. Hainsworth JD, Spigel DR, Markus TM, Shipley D, Thompson D, Rotman R, Dannaher C, Greco FA. Rituximab plus short-duration chemotherapy followed by Yttrium-90 Ibritumomab tiuxetan as first-line treatment for patients with follicular non-Hodgkin lymphoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma. 2009 Jun;9(3):223-8. link to original article contains verified protocol PubMed
  5. Zinzani PL, Tani M, Pulsoni A, De Renzo A, Stefoni V, Broccoli A, Montini GC, Fina M, Pellegrini C, Gandolfi L, Cavalieri E, Torelli F, Scopinaro F, Argnani L, Quirini F, Derenzini E, Rossi M, Pileri S, Fanti S, Baccarani M. A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by ?°Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. Ann Oncol. 2012 Feb;23(2):415-20. Epub 2011 May 2. link to original article contains verified protocol PubMed
  6. Provencio M, Cruz Mora MÁ, Gómez-Codina J, Quero Blanco C, Llanos M, García-Arroyo FR, de la Cruz L, Gumá Padró J, Delgado Pérez JR, Sánchez A, Alvarez Cabellos R, Rueda A; Gotel (Spanish Lymphoma Oncology Group). Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediate- and high-risk follicular lymphoma according to the follicular lymphoma international prognostic index: a multicenter, prospective phase II trial of the Spanish Lymphoma Oncology Group. Leuk Lymphoma. 2014 Jan;55(1):51-5. Epub 2013 Jun 12. link to original article PubMed
  7. Abstract: Armando Lopez-Guillermo, MD, PhD, Miguel A. Canales, MD, PhD, Ivan Dlouhy, Javier Briones, MD, Dolores Caballero, MD, PhD, Juan Manuel Sancho Sr., MD, Santiago Mercadal Vilchez, MD, Jose María Moraleda, MD, María José Terol, MD, PhD, Antonio Salar, MD, Luis Palomera, MD, Santiago Gardella, MD, Isidro Jarque, MD, Secundino Ferrer, Joan Bargay, MD, Andres Lopez, Carlos Panizo, Anna Muntanola, MD, Carlos Montalban, Eulogio Conde, MD, PhD, Miguel Hernandez, MD, Alfons Soler, Julian Marin, MD, Jose García Marco, Guillermo Deben and José Francisco Tomas, MD, PhD. A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization. Blood 2013 122:369. link to abstract

Interferon alfa-2a (Roferon-A)

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Regimen #1

Study Evidence
Salles et al. 2008 (FL2000) Non-randomized portion of RCT

Treatment preceded by R-CHVP+I versus CHVP+I.

Immunotherapy

Continuously for 18 months

Regimen #2

Study Evidence
Herold et al. 2007 Non-randomized portion of RCT

Treatment preceded by MCP or R-MCP.

Immunotherapy

Continuously until relapse

References

  1. Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, Dölken G, Naumann R, Knauf W, Freund M, Rohrberg R, Höffken K, Franke A, Ittel T, Kettner E, Haak U, Mey U, Klinkenstein C, Assmann M, von Grünhagen U; East German Study Group Hematology and Oncology Study. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007 May 20;25(15):1986-92. Epub 2007 Apr 9. link to original article contains verified protocol PubMed
  2. Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi JF, Haioun C, Brice P, Mahé B, Bouabdallah R, Audhuy B, Ferme C, Dartigeas C, Feugier P, Sebban C, Xerri L, Foussard C. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008 Dec 15;112(13):4824-31. Epub 2008 Sep 17. link to original article contains verified protocol PubMed
    1. Update: Bachy E, Houot R, Morschhauser F, Sonet A, Brice P, Belhadj K, Cartron G, Audhuy B, Fermé C, Feugier P, Sebban C, Delwail V, Maisonneuve H, Le Gouill S, Lefort S, Brousse N, Foussard C, Salles G; Groupe d'Etude des Lymphomes de l'Adulte (GELA). Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma. Haematologica. 2013 Jul;98(7):1107-14. Epub 2013 May 3. link to original article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Ghielmini et al. 2004 (SAKK 35/98) Phase III Rituximab Seems to have inferior EFS
Morschhauser et al. 2008 (FIT) Phase III Ibritumomab tiuxetan Inferior PFS
Hochster et al. 2009 (ECOG E1496) Phase III Rituximab Inferior PFS
Salles et al. 2010 (PRIMA) Phase III Rituximab Inferior PFS
Vitolo et al. 2013 Phase III Rituximab Seems not superior

No further treatment after induction therapy. Preceded by various treatments, see individual references for details.

References

  1. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
    1. Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article contains verified protocol PubMed
  2. Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article contains verified protocol PubMed
  3. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d'Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. link to original article contains protocol PubMed
    1. Update: Hagenbeek, Anton, Radford, John, Van Hoof, Achiel, Vitolo, Umberto, Rohatiner, Ama Z.S., Salles, Gilles, Soubeyran, Pierre, Tilly, Herve, Delaloye, Angelika Bischof, van Putten, Wim L.J., Morschhauser, Franck. 90Y-Ibritumomab Tiuxetan (Zevalin(R)) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients. ASH Annual Meeting Abstracts 2010 116: 594 link to abstract
    2. Update: Morschhauser F, Radford J, Van Hoof A, Botto B, Rohatiner AZ, Salles G, Soubeyran P, Tilly H, Bischof-Delaloye A, van Putten WL, Kylstra JW, Hagenbeek A. 90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial. J Clin Oncol. 2013 Jun 1;31(16):1977-83. Epub 2013 Apr 1. link to original article contains protocol PubMed
  4. 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 contains verified protocol PubMed
    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 PubMed
  5. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed
    1. Abstract: Update: Gilles Andre Salles, MD, PhD, John Francis Seymour, MBBS, FRACP, PhD, Pierre Feugier, MD, PhD, Fritz Offner, MD, Armando Lopez-Guillermo, MD, PhD, David Belada, M.D., Ph.D., Luc Xerri, MD, PhD, Reda Bouabdallah, MD, John Catalano, MBBS FRACP FRCPA, Brice Pauline, MD, Dolores Caballero, MD, PhD, Corinne Haioun, MD, PhD, Lars Moller Pedersen, Alain Delmer, MD, David Simpson, Sirpa Leppa, Pierre Soubeyran, Anton Hagenbeek, MD, PhD, Olivier Casasnovas, MD, Tanin Intragumtornchai, MD, Christophe Ferme, MD, Maria Gomes da Silva, Catherine Sebban, MD, Andrew Lister, Jane A Estell, MBBS, FRCPA, FRACP, Gustavo Milone, Anne Sonet, MD, Bertrand Coiffier, MD, PhD and Herve Tilly, MD. Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy. Blood 2013 122:509. link to abstract
    2. QoL Analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article PubMed
  6. Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F, Tucci A, Botto B, Chiappella A, Chiarenza A, Pinto A, De Renzo A, Zaja F, Castellino C, Bari A, Alvarez De Celis I, Evangelista A, Parvis G, Gamba E, Lobetti-Bodoni C, Ciccone G, Rossi G. Rituximab Maintenance Compared With Observation After Brief First-Line R-FND Chemoimmunotherapy With Rituximab Consolidation in Patients Age Older Than 60 Years With Advanced Follicular Lymphoma: A Phase III Randomized Study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Sep 20;31(27):3351-9. Epub 2013 Aug 19. link to original article contains verified protocol PubMed

Rituximab (Rituxan), Abbreviated Course

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Maintenance regimens of less than one year duration or less than 12 total doses.

Regimen #1

Study Evidence Comparator Efficacy
Vitolo et al. 2013 Phase III Observation Seems not superior

Treatment preceded by R-FND.

Chemotherapy

8-month course

Regimen #2

Study Evidence Comparator Efficacy
Ghielmini et al. 2004 (SAKK 35/98) Phase III Observation Seems to have superior EFS
Taverna et al. 2015 (SAKK 35/03) Phase III Rituximab x 5y Seems not superior

Treatment preceded by rituximab.

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once at week 12, months 5, 7, 9 (8 total doses, including the initial treatment)

Total treatment course of 9 months

Regimen #3

Study Evidence
Hainsworth et al. 2002 Phase II

Treatment preceded by rituximab.

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per week x 4 weeks; initial infusion rate of 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes, to a maximum rate of 300 mg/H

Supportive medications

4-week course

References

  1. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article contains protocol PubMed
  2. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
    1. Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article contains verified protocol PubMed
  3. Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. PubMed
  4. Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F, Tucci A, Botto B, Chiappella A, Chiarenza A, Pinto A, De Renzo A, Zaja F, Castellino C, Bari A, Alvarez De Celis I, Evangelista A, Parvis G, Gamba E, Lobetti-Bodoni C, Ciccone G, Rossi G. Rituximab Maintenance Compared With Observation After Brief First-Line R-FND Chemoimmunotherapy With Rituximab Consolidation in Patients Age Older Than 60 Years With Advanced Follicular Lymphoma: A Phase III Randomized Study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Sep 20;31(27):3351-9. Epub 2013 Aug 19. link to original article contains verified protocol PubMed
  5. Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Vanazzi A, Laszlo D, Raats J, Rauch D, Vorobiof DA, Lohri A, Biaggi Rudolf C, Rondeau S, Rusterholz C, Heijnen IA, Zucca E, Ghielmini M. Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03. J Clin Oncol. 2016 Feb 10;34(5):495-500. Epub 2015 Dec 28. link to original article contains verified protocol PubMed

Rituximab (Rituxan), Extended Course

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Maintenance regimens of one to two years duration or 12 to 16 total doses.

Regimen #1

Study Evidence Comparator Efficacy
Salles et al. 2010 (PRIMA) Phase III Observation Superior PFS

Starts 8 weeks after the last induction treatment with R-CHOP, R-CVP, or R-FCM.

Chemotherapy

8-week cycle for 12 cycles

Regimen #2

Study Evidence Comparator Efficacy
Hochster et al. 2009 (ECOG E1496) Phase III Observation Superior PFS

Treatment preceded by CVP x 6 to 8 cycles

Chemotherapy

Four courses, every 6 months (16 total doses)

Regimen #3

Study Evidence Comparator Efficacy
Ardeshna et al. 2014 Phase III Observation Superior TTNT
Rituximab induction, no maintenance Seems not superior

Treatment preceded by rituximab induction.

Chemotherapy

Given for two years (total of 16 doses)

Regimen #4

Study Evidence Comparator Efficacy
Rummel et al. 2014 (MAINTAIN) Phase III Rituximab x 4y TBD
Witzens-Harig et al. 2014 (MAXIMA) Non-randomized

Treatment in MAINTAIN preceded by BR x 6 and 2 doses of rituximab. Treatment in MAXIMA preceded by rituximab monotherapy or rituximab and chemotherapy (Most patients, 62%, received an anthracycline-based regimen).

Chemotherapy

Given for two years

References

  1. Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. PubMed
  2. 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 contains verified protocol PubMed
    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 PubMed
  3. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed
    1. Abstract: Update: Gilles Andre Salles, MD, PhD, John Francis Seymour, MBBS, FRACP, PhD, Pierre Feugier, MD, PhD, Fritz Offner, MD, Armando Lopez-Guillermo, MD, PhD, David Belada, M.D., Ph.D., Luc Xerri, MD, PhD, Reda Bouabdallah, MD, John Catalano, MBBS FRACP FRCPA, Brice Pauline, MD, Dolores Caballero, MD, PhD, Corinne Haioun, MD, PhD, Lars Moller Pedersen, Alain Delmer, MD, David Simpson, Sirpa Leppa, Pierre Soubeyran, Anton Hagenbeek, MD, PhD, Olivier Casasnovas, MD, Tanin Intragumtornchai, MD, Christophe Ferme, MD, Maria Gomes da Silva, Catherine Sebban, MD, Andrew Lister, Jane A Estell, MBBS, FRCPA, FRACP, Gustavo Milone, Anne Sonet, MD, Bertrand Coiffier, MD, PhD and Herve Tilly, MD. Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy. Blood 2013 122:509. link to abstract
    2. QoL Analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article PubMed
  4. Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, Warden J, Stevens L, Pocock CF, Miall F, Cunningham D, Davies J, Jack A, Stephens R, Walewski J, Ferhanoglu B, Bradstock K, Linch DC. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014 Apr;15(4):424-35. Epub 2014 Mar 4. link to original article contains verified protocol PubMed
  5. Witzens-Harig M, Foá R, Di Rocco A, van Hazel G, Chamone DF, Rowe JM, Arcaini L, Poddubnaya I, Ho AD, Ivanova V, Vranovsky A, Thurley D, Oertel S. Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study. Ann Hematol. 2014 Oct;93(10):1717-24. Epub 2014 May 14. Erratum in: Ann Hematol. 2014 Oct;93(10):1807. link to original article contains verified protocol PubMed
  6. Abstract: Mathias J. Rummel, MD, Andreas Viardot, Richard Greil, MD, Bernd Hertenstein, MD, Christian Lerchenmüller, MD, Arnold Ganser, Manfred Reeb, MD, Ulrich Kaiser, MD, Christina Balser, MD, Georg Maschmeyer, MD, Heinz Dürk, MD, Georg Schliesser, MD, Tobias Gaska, MD, Jan Dürig, MD, Axel C. Matzdorff, MD, Rudolf Weide, MD, Axel Hinke, PhD, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Jürgen Barth and Wolfram Brugger, MD. Bendamustine Plus Rituximab Followed By Rituximab Maintenance for Patients with Untreated Advanced Follicular Lymphomas. Results from the StiL NHL 7-2008 Trial (MAINTAIN trial) (ClinicalTrials.gov Identifier: NCT00877214). Blood 2014 124:3052. link to abstract

Rituximab (Rituxan), Very Extended Course

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Maintenance regimens of more than two years duration.

Regimen #1

Study Evidence Comparator Efficacy
Taverna et al. 2015 (SAKK 35/03) Phase III Rituximab x 9m Seems not superior

Treatment preceded by rituximab.

Chemotherapy

Given for up to 5 years, stop for disease progression or unacceptable toxicity

Regimen #2

Study Evidence Comparator Efficacy
Rummel et al. 2014 (MAINTAIN) Phase III Rituximab x 2y TBD

Treatment preceded by BR x 6 and 2 doses of rituximab

Chemotherapy

Given for four years

Regimen #3

Study Evidence Comparator Efficacy
Kahl et al. 2014 (RESORT) Phase III Salvage rituximab Seems not superior

Treatment preceded by rituximab.

Chemotherapy

Continued until treatment failure

References

  1. Abstract: Mathias J. Rummel, MD, Andreas Viardot, Richard Greil, MD, Bernd Hertenstein, MD, Christian Lerchenmüller, MD, Arnold Ganser, Manfred Reeb, MD, Ulrich Kaiser, MD, Christina Balser, MD, Georg Maschmeyer, MD, Heinz Dürk, MD, Georg Schliesser, MD, Tobias Gaska, MD, Jan Dürig, MD, Axel C. Matzdorff, MD, Rudolf Weide, MD, Axel Hinke, PhD, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Jürgen Barth and Wolfram Brugger, MD. Bendamustine Plus Rituximab Followed By Rituximab Maintenance for Patients with Untreated Advanced Follicular Lymphomas. Results from the StiL NHL 7-2008 Trial (MAINTAIN trial) (ClinicalTrials.gov Identifier: NCT00877214). Blood 2014 124:3052. link to abstract
  2. Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol. 2014 Oct 1;32(28):3096-102. Epub 2014 Aug 25. link to original article contains verified protocol PubMed
  3. Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Vanazzi A, Laszlo D, Raats J, Rauch D, Vorobiof DA, Lohri A, Biaggi Rudolf C, Rondeau S, Rusterholz C, Heijnen IA, Zucca E, Ghielmini M. Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03. J Clin Oncol. 2016 Feb 10;34(5):495-500. Epub 2015 Dec 28. link to original article contains verified protocol PubMed

Relapsed/refractory, randomized data

Bendamustine

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Regimen

Study Evidence Comparator Efficacy
Friedberg et al. 2008 Phase II
Kahl et al. 2010 Phase II
Sehn et al. 2016 (GADOLIN) Phase III Bendamustine & Obinutuzumab Inferior PFS

Chemotherapy

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

  • Bendamustine 120 mg/m2 IV over 60 to 120 minutes once per day on days 1 & 2

21 to 28-day cycle for 6 to 8 cycles (up to 12 in Friedberg et al. 2008)

References

  1. Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article contains verified protocol PubMed
  2. Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Cancer. 2010 Jan 1;116(1):106-14. link to original article contains verified protocol PubMed
  3. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. Epub 2016 Jun 23. link to original article contains protocol PubMed

Bendamustine & Obinutuzumab

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Regimen

Study Evidence Comparator Efficacy
Sehn et al. 2016 (GADOLIN) Phase III Bendamustine Superior PFS

Chemotherapy

  • Bendamustine 90 mg/m2 IV once per day on days 1 & 2
  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1000 mg IV once per day on days 1, 8, 15
    • Cycles 2 to 6: 1000 mg IV once on day 1

28-day cycle for 6 cycles

Treatment followed by obinutuzumab maintenance.

References

  1. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. Epub 2016 Jun 23. link to original article contains protocol PubMed

Bevacizumab & Rituximab

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Regimen

Study Evidence Comparator Efficacy
Hainsworth et al. 2014 Randomized Rituximab Seems to have superior PFS

Chemotherapy

  • Bevacizumab (Avastin) as follows:
    • 10 mg/kg IV once per day on days 3 & 15, then
    • 10 mg/kg IV once every 2 weeks for a total of 16 doses (start on week 12/month 3)
  • Rituximab (Rituxan) as follows:
    • 375 mg/m2 IV once per week x 4 weeks, then
    • 375 mg/m2 IV once every 2 months (months 3, 5, 7, 9)

One course

References

  1. Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J Jr, White L, Quinn R, DeBusk LM, Flinn IW. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):277-83. Epub 2014 Feb 28. link to original article contains verified protocol PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Matsumoto et al. 2015 (BRB) Phase II
Rummel et al. 2015 (StiL NHL 2-2003) Phase III FR Superior PFS

Note: in BRB, rituximab could be given on day 0, 1, 2, or 3 "according to the clinical convenience of each institution."

Chemotherapy

28-day cycle for up to 6 cycles (4 cycles in BRB)

References

  1. Matsumoto K, Takayama N, Aisa Y, Ueno H, Hagihara M, Watanabe K, Nakaya A, Chen K, Shimizu T, Tsukada Y, Yamada Y, Nakazato T, Ishida A, Miyakawa Y, Yokoyama K, Nakajima H, Masuda Y, Yano T, Okamoto S; Keio BRB Study Group. A phase II study of bendamustine plus rituximab in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma previously treated with rituximab: BRB study. Int J Hematol. 2015 Jun;101(6):554-62. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
  2. 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 contains protocol PubMed

Ibritumomab tiuxetan (Zevalin)

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Regimen

Study Evidence Comparator Efficacy
Witzig et al. 2002 Phase III Rituximab Superior ORR

For patients with relapsed or refractory disease

Chemoradiotherapy

8-day course of therapy

References

  1. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. link to original article contains verified protocol PubMed

Lenalidomide (Revlimid)

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Regimen

Study Evidence Comparator Efficacy
Leonard et al. 2015 (CALGB 50401) Phase III Lenalidomide & Rituximab Inferior TTP

Chemotherapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 15 mg PO once per day on days 1 to 21
    • Cycles 2 (if prior dose tolerated): 20 mg PO once per day on days 1 to 21
    • Cycles 3 to 12 (if prior dose tolerated): 25 mg PO once per day on days 1 to 21

Supportive medications

  • Aspirin or LMWH recommended for patients at high risk of thrombosis (see paper for details)

28-day cycle for 12 cycles

References

  1. Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, Czuczman M, Giguere JK, Cheson BD. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015 Nov 1;33(31):3635-40. Epub 2015 Aug 24. link to full article contains verified protocol PubMed

Lenalidomide & Rituximab

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Regimen

Study Evidence Comparator Efficacy
Leonard et al. 2015 (CALGB 50401) Phase III Lenalidomide Superior TTP

Chemotherapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 15 mg PO once per day on days 1 to 21
    • Cycles 2 (if prior dose tolerated): 20 mg PO once per day on days 1 to 21
    • Cycles 3 to 12 (if prior dose tolerated): 25 mg PO once per day on days 1 to 21
  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 8, 15, 22, 29 of cycle 1 only

Supportive medications

  • Aspirin or LMWH recommended for patients at high risk of thrombosis (see paper for details)

28-day cycle for 12 cycles

References

  1. Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, Czuczman M, Giguere JK, Cheson BD. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015 Nov 1;33(31):3635-40. Epub 2015 Aug 24. link to full article contains verified protocol PubMed

Obinutuzumab (Gazyva)

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Regimen

Study Evidence Comparator Efficacy
Sehn et al. 2015 (GAUSS) Randomized Phase II Rituximab Might have superior ORR

Chemotherapy

4-week course

Patients with CR, PR, or SD could proceed to maintenance obinutuzumab therapy.

References

  1. Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] contains verified protocol PubMed

R-CHOP

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

Regimen

Study Evidence Comparator Efficacy
Van Oers et al. 2006 (EORTC 20981) Phase III CHOP Superior PFS

Chemotherapy

21-day cycle for 6 cycles

Responders (PR or CR) were randomized to maintenance rituximab versus no further treatment.

References

  1. van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
    1. Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article contains verified protocol PubMed

R-FCM

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R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study Evidence Comparator Efficacy
Forstpointner et al. 2004 Phase III FCM Seems to have superior PFS

Chemotherapy

28-day cycle for 4 cycles

Responders (PR or CR) were randomized to maintenance rituximab or no further treatment.

References

  1. Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article contains verified protocol PubMed
    1. Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article contains verified protocol PubMed

Rituximab (Rituxan)

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Regimen #1

Study Evidence Comparator Efficacy
Hainsworth et al. 2014 Randomized Bevacizumab & Rituximab Seems to have inferior PFS

Chemotherapy

  • Rituximab (Rituxan) as follows:
    • 375 mg/m2 IV once per week x 4 weeks, then
    • 375 mg/m2 IV once every 2 months (months 3, 5, 7, 9)

One course

Regimen #2

Study Evidence Comparator Efficacy
McLaughlin et al. 1998 Phase II
Witzig et al. 2002 Phase III Ibritumomab tiuxetan Inferior ORR
Ghielmini et al. 2004 (SAKK 35/98) Non-randomized portion of RCT
Hainsworth et al. 2005 Non-randomized portion of RCT
Sehn et al. 2015 (GAUSS) Randomized Phase II Obinutuzumab Might have inferior ORR

Chemotherapy

Supportive medications

4-week course

Patients with response or stable disease at 12 weeks in SAKK 35/98 were randomized to maintenance rituximab or no further treatment. Patients with response or stable disease in Hainsworth et al. 2005 were randomized to maintenance rituximab or re-treatment with rituximab at time of progression. Patients with CR/PR/SD in GAUSS could proceed to receive maintenance rituximab.

Regimen #3

Study Evidence Comparator Efficacy
Coiffier et al. 2011 (LYM-3001) Phase III VR Seems to have inferior PFS

Chemotherapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 6: 375 mg/m2 IV once on day 1

Supportive medications

5-week cycle for 6 cycles

Regimen #4

Study Evidence Comparator Efficacy
Kahl et al. 2014 (RESORT) Phase III Indefinite rituximab Seems not superior

Treatment preceded by rituximab.

Chemotherapy

4-week course, repeated every progression until treatment failure

References

  1. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article contains verified protocol PubMed
  2. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. link to original article contains verified protocol PubMed
  3. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
    1. Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article contains verified protocol PubMed
  4. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Feb 20;23(6):1088-95. Epub 2005 Jan 18. link to original article contains protocol PubMed
  5. Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011 Aug;12(8):773-84. Epub 2011 Jul 1. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012 Oct 22;5:67. link to original article PubMed
  6. Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol. 2014 Oct 1;32(28):3096-102. Epub 2014 Aug 25. link to original article contains verified protocol PubMed
  7. Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J Jr, White L, Quinn R, DeBusk LM, Flinn IW. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):277-83. Epub 2014 Feb 28. link to original article contains verified protocol PubMed
  8. Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] contains verified protocol PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Regimen

Study Evidence Comparator Efficacy
Coiffier et al. 2011 (LYM-3001) Phase III Rituximab Seems to have superior PFS

Chemotherapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV push over 3 to 5 seconds once per day on days 1, 8, 15, 22
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

Supportive medications

  • No routine antiviral prophylaxis was mandated

35-day cycle for 5 cycles

References

  1. Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011 Aug;12(8):773-84. Epub 2011 Jul 1. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012 Oct 22;5:67. link to original article PubMed

Relapsed/refractory, non-randomized or retrospective data

Bortezomib (Velcade)

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Regimen

Study Evidence
O'Connor et al. 2005 Phase II, <20 patients reported

Chemotherapy

Supportive medications

  • "Use of antiemetics, erythropoietin, and Filgrastim (Neupogen) was allowed if deemed necessary by the treating physician."

21-day cycles

References

  1. O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2005 Feb 1;23(4):676-84. Epub 2004 Dec 21. link to original article contains verified protocol PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence
Rummel et al. 2005 Phase II
Robinson et al. 2008 Phase II

Chemotherapy

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

  • Rituximab (Rituxan) as follows:
    • One week prior to start of cycle 1: 375 mg/m2 IV once
    • Cycles 1 to 4: 375 mg/m2 IV once on day 1
    • 4 weeks after cycle 4: 375 mg/m2 IV once
  • Bendamustine 90 mg/m2 IV over 30 to 60 minutes once per day on days 2 & 3

28-day cycle for 4 cycles

Robinson et al. 2008 said that patients "could receive up to six cycles if disease regression was evident between the second and fourth cycles".

References

  1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article contains verified protocol PubMed
  2. Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9. Epub 2008 Jul 14. link to original article contains verified protocol PubMed

BVR

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BVR: Bendamustine, Velcade (Bortezomib), Rituximab

Regimen #1

Study Evidence
Friedberg et al. 2011 Phase II

Chemotherapy

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

  • Bendamustine 90 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 4, given last
  • Bortezomib (Velcade) 1.3 mg/m2 IV push once per day on days 1, 4, 8, 11, given first
  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given after bortezomib and before bendamustine

Supportive medications

  • Premedications, antiemetic therapy, and growth factor support per institutional guidelines
  • No routine antibiotic or antiviral prophylaxis was given

28-day cycle for 6 cycles

Regimen #2

Study Evidence
Fowler et al. 2011 (VERTICAL) Phase II

Chemotherapy

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

  • Bendamustine 50 to 90 mg/m2 IV over 60 minutes once per day on days 1 & 2, given after bortezomib and before rituximab
  • Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22, given first
  • Rituximab (Rituxan) given last, as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

Supportive medications

  • Antiviral prophylaxis at physician discretion

35-day cycle for 5 cycles

References

  1. Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, Grant S, Leonard JP. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011 Mar 10;117(10):2807-12. Epub 2011 Jan 14. link to original article contains protocol PubMed
  2. Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011 Sep 1;29(25):3389-95. Epub 2011 Aug 1. link to original article contains protocol PubMed

Dexamethasone, Lenalidomide, Rituximab

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Regimen

Study Evidence
Ahmadi et al. 2014 Phase II

Chemotherapy

28-day cycle, continued until progression or intolerance

FR

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FR: Fludarabine, Rituximab

Regimen

Study Evidence
Czuczman et al. 2005 Phase II

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Weeks 2, 6, 10, 14, 18, 22: 25 mg/m2 IV once per day on days 1 to 5
  • Rituximab (Rituxan) as follows:
    • Weeks 1 & 26: 375 mg/m2 IV once per day on days 1 & 4
    • Weeks 6, 14, 22: 375 mg/m2 IV once 72 hours before day 1

26-week course

References

  1. Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, Bernstein ZP, McCarthy P, Alam A, Hernandez-Ilizaliturri F, Skipper M, Brown K, Chanan-Khan A, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-Lopez A, Bernstein SH. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005 Feb 1;23(4):694-704. link to original article contains verified protocol PubMed

Ibritumomab tiuxetan (Zevalin)

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Regimen

Study Evidence
Witzig et al. 2002 Phase II

For patients with rituximab-refractory disease

Chemoradiotherapy

8-day course of therapy

References

  1. Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A, Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, Grillo-López AJ. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3793-803. link to original article contains verified protocol PubMed
  2. Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002 Aug 1;20(15):3262-9. link to original article contains verified protocol PubMed

Ibrutinib (Imbruvica)

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Regimen

Study Evidence
Bartlett et al. 2014 Phase II

Chemotherapy

Continued until progression or unacceptable toxicity

References

  1. Abstract: Nancy L. Bartlett, MD, Betsy R. LaPlant, MS, Jing Qi, MD, PhD, Stephen M. Ansell, MD, PhD, John G. Kuruvilla, MD, Craig B. Reeder, MD, Lim S. Thye, MD, Daniel M. Anderson, MD, MPH, Charles Erlichman, MD and Barry A. Siegel, MD. Ibrutinib Monotherapy in Relapsed/Refractory Follicular Lymphoma (FL): Preliminary Results of a Phase 2 Consortium (P2C) Trial. Blood 2014 124:800. link to abstract

Idelalisib (Zydelig)

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On 3/21/2016 Gilead announced that they were stopping seven clinical trials of idelalisib in patients with CLL, SLL, and iNHL due to excess deaths and increased rates of SAEs. A REMS program has also been announced.

Regimen

Study Evidence
Gopal et al. 2014 (DELTA) Phase II

Chemotherapy

Continued until progression, death, or unacceptable toxicity

References

  1. 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 PMC article link to original article contains verified protocol PubMed
    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

Lenalidomide (Revlimid)

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Regimen

Study Evidence
Witzig et al. 2009 (NHL-001) Phase II

Chemotherapy

28-day cycles until disease progression or unacceptable toxicity

References

  1. Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article contains verified protocol PubMed

Lenalidomide & Rituximab

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Regimen #1

Study Evidence
Tuscano et al. 2014 Phase II

Chemotherapy

Supportive medications

28-day cycle for 2 cycles

Responders proceeded to lenalidomide maintenance. For patients with less than a CR after induction, more rituximab could be given at the discretion of the treating physician. Dosing details not provided in the reference.

Regimen #2

Study Evidence
Chong et al. 2015 Phase II

Chemotherapy

28-day cycles until progression or intolerance

References

  1. Tuscano JM, Dutia M, Chee K, Brunson A, Reed-Pease C, Abedi M, Welborn J, O'Donnell RT. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014 May;165(3):375-81. Epub 2014 Mar 7. link to original article contains verified protocol PubMed
  2. Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. Epub 2015 Jan 28. link to original article contains verified protocol PubMed

Obinutuzumab (Gazyva)

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Regimen

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

Note: Dose here is that recommended by the publication as having "encouraging activity with an acceptable safety profile"

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1600 mg (diluted to 10 mg/mL) IV once per day on days 1 & 7
    • Cycles 2 to 8: 800 mg IV once on day 1
    • Initial infusion rate is 50 mg/hour. In the absence of infusion-related reactions (IRRs), the rate is then increased by 50 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.

Supportive medications

  • Acetaminophen (Tylenol) (no dose specified) PO 30 minutes before first infusion
  • Antihistamine (no drug or dose specified) PO 30 minutes before first infusion
  • Corticosteroids before first infusion for patients at "high risk" of infusion reaction

21-day cycle for 8 cycles

References

  1. Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Results From the Phase II GAUGUIN Study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article contains verified protocol PubMed

Ofatumumab (Arzerra)

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Regimen

Study Evidence
Czucman et al. 2012 (405 Study) Phase II

Chemotherapy

  • Ofatumumab (Arzerra) 300 mg IV once on week 1 (dose 1); then 1000 mg IV once per week thereafter (doses 2 to 8)

Supportive medications

8-week total course

References

  1. Hagenbeek A, Gadeberg O, Johnson P, Pedersen LM, Walewski J, Hellmann A, Link BK, Robak T, Wojtukiewicz M, Pfreundschuh M, Kneba M, Engert A, Sonneveld P, Flensburg M, Petersen J, Losic N, Radford J. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood. 2008 Jun 15;111(12):5486-95. Epub 2008 Apr 4. link to original article PubMed
  2. Czuczman MS, Fayad L, Delwail V, Cartron G, Jacobsen E, Kuliczkowski K, Link BK, Pinter-Brown L, Radford J, Hellmann A, Gallop-Evans E, DiRienzo CG, Goldstein N, Gupta I, Jewell RC, Lin TS, Lisby S, Schultz M, Russell CA, Hagenbeek A; 405 Study Investigators. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012 Apr 19;119(16):3698-704. Epub 2012 Mar 2. link to original article contains verified protocol PubMed

PEP-C

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PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Regimen

Study Evidence
Coleman et al. 2008 Phase II

Induction phase

Supportive medications

Continue until WBC less than 3 x 109/L, hold until WBC recovery, then titrate in maintenance phase per paper (see publication for details)

Maintenance phase

  • Same medications and doses given per day as used in the induction phase, but the number of days per week they are used is titrated to maintain a WBC of at least 3; for example, 5 out of 7 days, every other day, once per week, etc.

References

  1. Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, George P, Kaufman TP, Leonard JP. Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory lymphoma: low-dose metronomic, multidrug therapy. Cancer. 2008 May 15;112(10):2228-32. link to original article contains verified protocol PubMed
  2. Coleman M, Ruan G, Elstrom RL, Martin P, Leonard JP. Metronomic therapy for refractory/relapsed lymphoma: the PEP-C low-dose oral combination chemotherapy regimen. Hematology. 2012 Apr;17 Suppl 1:S90-2. PubMed

R-CHOP

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

Regimen

Study Evidence
Czuczman et al. 1999 Phase II

Chemotherapy

21-day cycle for 6 cycles

References

  1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article contains protocol PubMed
    1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed

R-CHOP -> Ibritumomab tiuxetan

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Regimen

Study Evidence
Illidge et al. 2016 (UK NCRI LG) Phase II

Patients received R-CHOP or R-CVP prior to ibritumomab tiuxetan; this was not a randomization. Dosing details for R-CHOP were not available in the abstract; this is a typical R-CHOP regimen.

Chemotherapy, R-CHOP portion

21-day cycle for 3 cycles, followed by:

Chemoradiotherapy

8-day course of therapy

References

  1. Illidge TM, McKenzie HS, Mayes S, Bates A, Davies AJ, Pettengell R, Stanton L, Cozens K, Hampson G, Dive C, Zivanovic M, Tipping J, Gallop-Evans E, Radford JA, Johnson PW. Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study. Br J Haematol. 2016 Apr;173(2):274-82. Epub 2016 Feb 5. link to original article contains protocol PubMed

R-CVP -> Ibritumomab tiuxetan

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

Study Evidence
Illidge et al. 2016 (UK NCRI LG) Phase II

Patients received R-CHOP or R-CVP prior to ibritumomab tiuxetan; this was not a randomization. Dosing details for R-CVP were not available in the abstract; this is a typical R-CVP regimen.

Chemotherapy, R-CVP portion

21-day cycle for 3 cycles, followed by:

Chemoradiotherapy

8-day course of therapy

References

  1. Illidge TM, McKenzie HS, Mayes S, Bates A, Davies AJ, Pettengell R, Stanton L, Cozens K, Hampson G, Dive C, Zivanovic M, Tipping J, Gallop-Evans E, Radford JA, Johnson PW. Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study. Br J Haematol. 2016 Apr;173(2):274-82. Epub 2016 Feb 5. link to original article contains protocol PubMed

R-DexaBEAM

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

Regimen

Study Evidence
Kirschey et al. 2014 Phase II

Chemotherapy

3- to 4-week cycle for 2 cycles

Patient proceed to undergo high dose therapy and autologous stem cell transplant.

References

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

R-FND

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R-FND: Rituximab, Fludarabine, Novantrone, Dexamethasone

Regimen

Chemotherapy

28-day cycle for up to 8 cycles

References

  1. McLaughlin P, Hagemeister FB, Rodriguez MA, Sarris AH, Pate O, Younes A, Lee MS, Dang NH, Romaguera JE, Preti AH, McAda N, Cabanillas F. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol. 2000 Dec;27(6 Suppl 12):37-41. PubMed
  2. Abstract: P. McLaughlin, M. A. Rodriguez, F. B. Hagemeister, J. Romaguera, A. H. Sarris, A. Younes, N. H. Dang, A. Goy, F. Samaniego, M. Hess et al. Stage IV indolent lymphoma: A randomized study of concurrent vs. sequential use of FND chemotherapy (fludarabine, mitoxantrone, dexamethasone) and rituximab (R) monoclonal antibody therapy, with interferon maintenance. 2003 ASCO Annual Meeting Abstract 2269. link to abstract contains verified dosages
  3. Hagemeister F, Cabanillas F, Coleman M, Gregory SA, Zinzani PL. The role of mitoxantrone in the treatment of indolent lymphomas. Oncologist. 2005 Feb;10(2):150-9. link to original article PubMed content property of HemOnc.org
  4. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, Romaguera J, Rodriguez MA, Tsimberidou AM, Verstovsek S, Younes A, Pro B, Lee MS, Ayala A, McLaughlin P. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006 Apr 1;24(10):1582-9. link to original article PubMed
  5. Abstract: G. E. Manoukian, F. B. Hagemeister, P. McLaughlin, L. Fayad, F. Samaniego, A. Goy, J. E. Romaguera, B. Pro, F. Cabanillas, M. A. Rodriguez. Rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) for patients with relapsed indolent B-cell lymphoma (RIL). 2010 ASCO Annual Meeting Abstract 8078. link to abstract contains verified dosages

Rituximab & Vorinostat

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Regimen

Study Evidence
Chen et al. 2015 Phase II, <20 patients in this subgroup

Chemotherapy

21-day cycles until progression or two cycles past documented CR

References

  1. Chen R, Frankel P, Popplewell L, Siddiqi T, Ruel N, Rotter A, Thomas SH, Mott M, Nathwani N, Htut M, Nademanee A, Forman SJ, Kirschbaum M. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma. Haematologica. 2015 Mar;100(3):357-62. Epub 2015 Jan 16. link to original article contains verified protocol PubMed

Temsirolimus (Torisel)

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Regimen

Study Evidence
Smith et al. 2010 Phase II

Chemotherapy

28-day cycle for minimum of 2 cycles

References

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

VBR

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VBR: Velcade (Bortezomib), Bendamustine, Rituximab

Regimen #1

Study Evidence
Fowler et al. 2011 (VERTICAL) Phase II

Bendamustine was dose-escalated in the first phase of the trial and the 90 mg/m2 dose is the MTD.

Chemotherapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22, given first
  • Bendamustine 90 mg/m2 IV once per day on days 1 & 2, given second
  • Rituximab (Rituxan) given last, as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

35-day cycle for 5 cycles

Regimen #2

Study Evidence
Friedberg et al. 2011 Phase II, <20 patients in this subgroup

Chemotherapy

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

28-day cycle for 6 cycles

References

  1. Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, Grant S, Leonard JP. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011 Mar 10;117(10):2807-12. Epub 2011 Jan 14. link to original article contains verified protocol PubMed
  2. Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011 Sep 1;29(25):3389-95. Epub 2011 Aug 1. link to original article contains verified protocol PubMed

Vorinostat (Zolinza)

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Regimen

Study Evidence
Kirschbaum et al. 2011 Phase II, <20 pts in subgroup
Ogura et al. 2014 Phase II

Chemotherapy

21-day cycles until progression or unacceptable toxicity

References

  1. Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, Matsuoka D, Pulone B, Rotter AJ, Espinoza-Delgado I, Nademanee A, Forman SJ, Gandara D, Newman E. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2011 Mar 20;29(9):1198-203. Epub 2011 Feb 7. link to original article contains verified protocol PubMed
  2. Ogura M, Ando K, Suzuki T, Ishizawa K, Oh SY, Itoh K, Yamamoto K, Au WY, Tien HF, Matsuno Y, Terauchi T, Yamamoto K, Mori M, Tanaka Y, Shimamoto T, Tobinai K, Kim WS. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Br J Haematol. 2014 Jun;165(6):768-776. Epub 2014 Mar 12. link to original article contains verified protocol PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Regimen #1

Study Evidence
Agathocleous et al. 2010 Phase II

Chemotherapy

35-day cycle for up to 6 cycles

Regimen #2

Study Evidence
de Vos et al. 2009 Phase II

Chemotherapy

35-day cycle for 3 cycles

Regimen #3

Study Evidence
Baiocchi et al. 2011 Phase II, <20 patients reported

Bortezomib dose was initially 1.5 mg/m2 but was reduced due to excess grade 3 neurotoxicity.

Chemotherapy

21-day cycle for up to 5 cycles.

Patients without progression could receive VR maintenance

References

  1. de Vos S, Goy A, Dakhil SR, Saleh MN, McLaughlin P, Belt R, Flowers CR, Knapp M, Hart L, Patel-Donnelly D, Glenn M, Gregory SA, Holladay C, Zhang T, Boral AL. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol. 2009 Oct 20;27(30):5023-30. Epub 2009 Sep 21. link to original article contains verified protocol PubMed
  2. Agathocleous A, Rohatiner A, Rule S, Hunter H, Kerr JP, Neeson SM, Matthews J, Strauss S, Montoto S, Johnson P, Radford J, Lister A. Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia. Br J Haematol. 2010 Nov;151(4):346-53. Epub 2010 Sep 29. link to original article contains verified protocol PubMed
  3. Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. link to original article contains verified protocol PubMed

VR-CP

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VR-CP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Prednisone

Regimen

Study Evidence
Craig et al. 2014 Phase II

Chemotherapy

Supportive medications

  • Antiviral prophylaxis against VZV recommended for all patients

21-day cycle for 6 cycles

References

  1. Craig M, Hanna WT, Cabanillas F, Chen CS, Esseltine DL, Neuwirth R, O'Connor OA. Phase II study of bortezomib in combination with rituximab, cyclophosphamide and prednisone with or without doxorubicin followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma. Br J Haematol. 2014 Sep;166(6):920-8. Epub 2014 Jul 9. link to original article contains verified protocol PubMed

Consolidation and/or maintenance after salvage therapy

Allogeneic stem cell transplant

To be completed. Usually reserved for younger and very fit individuals; preceded by a high-intensity salvage chemotherapy such as those used for DLBCL. See details about preparative regimens.

FCR

Study Evidence
Khouri et al. 2001 Phase II

FCR: Fludarabine, Cyclophosphamide, Rituximab
Details are from Khouri et al. 2008.

Preparative regimen

GVHD prophylaxis

(90)YFC

Study Evidence
Khouri et al. 2012 Non-randomized

(90)YFC: Ibritumomab tiuxetan, Fludarabine, Cyclophosphamide

Preparative regimen

GVHD prophylaxis

References

  1. Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595-9. link to original article PubMed
    1. Update: Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. Epub 2008 Apr 14. Erratum in: Blood. 2009 Feb 12;113(7):1613. link to original article contains verified protocol PubMed
    2. Update: Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. link to original article contains verified protocol PubMed

Autologous stem cell transplant

To be completed. Usually preceded by a high-intensity salvage chemotherapy such as those used for DLBCL. See details about preparative regimens.

Lenalidomide (Revlimid)

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Regimen

Study Evidence
Tuscano et al. 2014 Phase II

Treatment preceded by lenalidomide and rituximab.

Chemotherapy

Supportive medications

28-day cycles until progression or excess toxicity

References

  1. Tuscano JM, Dutia M, Chee K, Brunson A, Reed-Pease C, Abedi M, Welborn J, O'Donnell RT. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014 May;165(3):375-81. Epub 2014 Mar 7. link to original article contains verified protocol PubMed

Obinutuzumab (Gazyva)

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Regimen

Study Evidence
Sehn et al. 2015 (GAUSS) Non-randomized portion of RCT
Sehn et al. 2016 (GADOLIN) Non-randomized portion of RCT

Treatment in GAUSS preceded by salvage obinutuzumab induction. Treatment in GADOLIN preceded by salvage benadmustine & obinutuzumab x 6.

Chemotherapy

Up to 2-year course

References

  1. Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] contains verified protocol PubMed
  2. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. Epub 2016 Jun 23. link to original article contains protocol PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Ghielmini et al. 2004 (SAKK 35/98) Phase III Rituximab Seems to have inferior EFS
Forstpointner et al. 2004 Phase III Rituximab Seems to have inferior PFS
van Oers et al. 2006 (EORTC 20981) Phase III Rituximab Seems to have inferior OS

No further treatment after salvage therapy. Preceded by various treatments, see individual references for details.

References

  1. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
    1. Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article contains verified protocol PubMed
  2. Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article contains verified protocol PubMed
    1. Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article contains verified protocol PubMed
  3. van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
    1. Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article contains verified protocol PubMed

Rituximab (Rituxan), Abbreviated Course

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Maintenance regimens of less than one year duration or less than 12 total doses.

Regimen #1

Study Evidence Comparator Efficacy
Forstpointner et al. 2004 Phase III Observation Seems to have superior PFS

Treatment preceded by salvage FCM for relapsed/refractory disease.

Chemotherapy

Two courses at 3 and 9 months after completion of salvage therapy (8 total doses)

Regimen #2

Study Evidence Comparator Efficacy
Ghielmini et al. 2004 (SAKK 35/98) Phase III Observation Seems to have superior EFS

Treatment preceded by salvage rituximab.

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once at week 12, months 5, 7, 9 (8 total doses, including the initial treatment)

Total treatment course of 9 months

References

  1. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
    1. Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article contains verified protocol PubMed
  2. Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article contains verified protocol PubMed
    1. Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article contains verified protocol PubMed

Rituximab (Rituxan), Extended Course

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Maintenance regimens of one to two years duration or 12 to 16 total doses.

Regimen #1, 3-month cycles

Study Evidence Comparator Efficacy
van Oers et al. 2006 (EORTC 20981) Phase III Observation Seems to have superior OS

Treatment preceded by salvage CHOP versus salvage R-CHOP for relapsed/refractory disease.

Chemotherapy

3-month cycles until relapse or for a maximum of 2 years

Regimen #2, 2-month cycles

Study Evidence
Witzens-Harig et al. 2014 (MAXIMA) Non-randomized
Sehn et al. 2015 (GAUSS) Non-randomized portion of RCT

Treatment in MAXIMA preceded by salvage rituximab monotherapy or salvage rituximab and chemotherapy (Most patients, 62%, received an anthracycline-based regimen). Treatment in GAUSS preceded by salvage rituximab monotherapy.

Chemotherapy

Given for up to two years

References

  1. van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
    1. Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article contains verified protocol PubMed
  2. Witzens-Harig M, Foá R, Di Rocco A, van Hazel G, Chamone DF, Rowe JM, Arcaini L, Poddubnaya I, Ho AD, Ivanova V, Vranovsky A, Thurley D, Oertel S. Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study. Ann Hematol. 2014 Oct;93(10):1717-24. Epub 2014 May 14. Erratum in: Ann Hematol. 2014 Oct;93(10):1807. link to original article contains verified protocol PubMed
  3. Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] contains verified protocol PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Regimen

Study Evidence
Baiocchi et al. 2011 Phase II, <20 patients reported

Treatment preceded by salvage VR.

Chemotherapy

6-month cycle for up to 2 years

References

  1. Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. link to original article contains verified protocol PubMed

Prognosis

Follicular lymphoma international prognostic index (FLIPI - 1)

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Each category is assigned 0 or 1 points:

  • Age
    • Less than 60 years (0 points)
    • Greater than or equal to 60 years (1 point)
  • Ann Arbor stage
    • I or II (0 points)
    • III or IV (1 point)
  • Hemoglobin level
    • Less than 12 g/dL (1 point)
    • Greater than or equal to 12 g/dL (0 points)
  • Serum LDH level (note that reference ranges can vary widely!)
    • Less than or equal to upper limit of normal (0 points)
    • Greater than upper limit of normal (1 point)
  • Number of nodal sites
    • Less than 5 (0 points)
    • Greater than or equal to 5 (1 point)

Risk stratification:

  • 0 or 1 points: Low risk
  • 2 points: Intermediate risk
  • Greater than or equal to 3 points: High risk

References

  1. Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, Bellei M, Brice P, Caballero D, Coiffier B, Conde-Garcia E, Doyen C, Federico M, Fisher RI, Garcia-Conde JF, Guglielmi C, Hagenbeek A, Haïoun C, LeBlanc M, Lister AT, Lopez-Guillermo A, McLaughlin P, Milpied N, Morel P, Mounier N, Proctor SJ, Rohatiner A, Smith P, Soubeyran P, Tilly H, Vitolo U, Zinzani PL, Zucca E, Montserrat E. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1;104(5):1258-65. Epub 2004 May 4. link to original article PubMed

Follicular lymphoma international prognostic index (FLIPI - 2)

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Each category is assigned 0 or 1 points:

  • Age
    • Less than 60 years (0 points)
    • Greater than or equal to 60 years (1 point)
  • Hemoglobin level
    • Less than 12 g/dL (1 point)
    • Greater than or equal to 12 g/dL (0 points)
  • β2-microglobulin level (note that reference ranges can vary)
    • Less than or equal to upper limit of normal (0 points)
    • Greater than upper limit of normal (1 point)
  • Longest diameter of the largest involved node
    • Less than or equal to 6 cm (0 points)
    • Greater than 6 cm (1 point)
  • Bone marrow involvement
    • No (0 points)
    • Yes (1 point)

Risk stratification:

  • 0 points: Low risk
  • 1 or 2 points: Intermediate risk
  • Greater than or equal to 3 points: High risk

References

  1. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, Pro B, Pileri S, Pulsoni A, Soubeyran P, Cortelazzo S, Martinelli G, Martelli M, Rigacci L, Arcaini L, Di Raimondo F, Merli F, Sabattini E, McLaughlin P, Solal-Céligny P. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009 Sep 20;27(27):4555-62. Epub 2009 Aug 3. link to original article PubMed

Response criteria

NCI Sponsored International Working Group Criteria (1999)

  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

Investigational agents

These are drugs under study with at least some promising results for this disease.