Follicular lymphoma

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Sanjai Sharma, MD
Sequoia Regional Cancer Center
Visalia, CA

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75 regimens on this page
122 variants on this page

Contents


Guidelines

ESMO

Current

Older

NCCN

Early disease, definitive therapy

Ibritumomab tiuxetan monotherapy

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Regimen

Study Evidence
Samaniego et al. 2014 Phase II

Radioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8, given first
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) given second, as follows:
    • Platelet count greater than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV once on day 8
    • Platelet count between 100 and 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV once on day 8

References

  1. 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

Radiation therapy

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Yahalom et al. 1993
Kelsey et al. 1994 Non-randomized portion of RCT
Lowry et al. 2011 Phase III (E) RT x 40 to 45 Gy Seems not superior
Hoskin et al. 2014 (FORT) Phase III (C) RT x 4 Gy Superior TTP
MacManus et al. 2018 (TROG 99.03) Non-randomized portion of RCT

This is the current "standard dose" radiotherapy - dose varies per protocol and location radiated.

Radiotherapy

Subsequent treatment

References

  1. Yahalom J, Varsos G, Fuks Z, Myers J, Clarkson BD, Straus DJ. Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma: results of a prospective randomized study. Cancer. 1993 Apr 1;71(7):2342-50. link to original article PubMed
  2. Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol. 1994;11(1):19-25. link to original article PubMed
  3. Lowry L, Smith P, Qian W, Falk S, Benstead K, Illidge T, Linch D, Robinson M, Jack A, Hoskin P. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol. 2011 Jul;100(1):86-92. Epub 2011 Jun 12. link to original article PubMed
  4. FORT: Hoskin PJ, Kirkwood AA, Popova B, Smith P, Robinson M, Gallop-Evans E, Coltart S, Illidge T, Madhavan K, Brammer C, Diez P, Jack A, Syndikus I. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol. 2014 Apr;15(4):457-63. Epub 2014 Feb 24. link to original article PubMed
  5. TROG 99.03: MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D, Jayamohan J, Seymour JF. Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol. 2018 Oct 10;36(29):2918-2925. Epub 2018 Jul 5. link to original article PubMed

Early disease, adjuvant therapy

Observation

Regimen

Study Evidence Comparator Comparative Efficacy
Kelsey et al. 1994 Randomized (C) CHOP x 6 Seems to have inferior RFS
Kelsey et al. 1994 Randomized (C) Chlorambucil Seems not superior
MacManus et al. 2018 (TROG 99.03) Randomized (C) 1. CVP
2. R-CVP
Seems to have inferior PFS

No further treatment. Note that in TROG 99.03, patients enrolled after 2006 were randomized between this arm and R-CVP.

Preceding treatment

References

  1. Yahalom J, Varsos G, Fuks Z, Myers J, Clarkson BD, Straus DJ. Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma: results of a prospective randomized study. Cancer. 1993 Apr 1;71(7):2342-50. link to original article PubMed
  2. Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol. 1994;11(1):19-25. link to original article PubMed
  3. TROG 99.03: MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D, Jayamohan J, Seymour JF. Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol. 2018 Oct 10;36(29):2918-2925. Epub 2018 Jul 5. link to original article PubMed

Advanced disease, pre-phase

Rituximab monotherapy

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Regimen

Study Evidence
Hainsworth et al. 2005a Phase II
Hainsworth et al. 2009 Phase II

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

Chemotherapy

28-day course

Subsequent treatment

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
  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 SD article contains verified protocol PubMed

Advanced disease, first-line therapy, randomized data

Bendamustine & Obinutuzumab

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G-B: Gazyva (Obinutuzumab) & Bendamustine

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2017 (GALLIUM) Phase III (E) See link See link See link

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

Subsequent treatment

References

  1. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed

BR

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

Variant #1, 6 cycles

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Rummel et al. 2013 (StiL NHL1) Phase III (E) R-CHOP Superior PFS
Marcus et al. 2017 (GALLIUM) Phase III (C) See link See link See link
Morschhauser et al. 2018 (RELEVANCE) Phase III (C) Lenalidomide & Rituximab Seems not superior Different toxicity

Chemotherapy

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

Subsequent treatment

Variant #2, 6 cycles with rituximab extension

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

Chemotherapy

28-day cycle for 8 cycles

Subsequent treatment

Variant #3, 8 cycles

Study Evidence Comparator Comparative Efficacy
Flinn et al. 2014 (BRIGHT) Phase III (E) 1. R-CHOP
2. R-CVP
Superior PFS (*)

Efficacy in BRIGHT is based on the 2019 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

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 8 cycles

References

  1. StiL NHL1: 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; 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. BRIGHT: 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 link to PMC article PubMed
    1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
  3. 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
  4. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed
  5. RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article contains verified protocol in supplement PubMed

Chlorambucil monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Ardeshna et al. 2003 Phase III (C) Observation Seems not superior

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

Chemotherapy

Continued indefinitely

References

  1. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson GV, 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 monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Peterson et al. 2003 (CALGB 7951) Phase III (E) CHOP-B Seems not superior
Smith et al. 2009 (CALGB 8691) Phase III (C) Cyclophosphamide & Interferon alfa-2a Seems not superior

Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

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. CALGB 7951: 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
  2. CALGB 8691: Smith SM, Johnson J, Cheson BD, Canellos G, Petroni G, Oken M, Duggan D, Hurd D, Gockerman JP, Parker B, Prchal J, Peterson BA; Cancer and Leukemia Group B; Eastern Cooperative Oncology Group. Recombinant interferon-alpha2b added to oral cyclophosphamide either as induction or maintenance in treatment-naive follicular lymphoma: final analysis of CALGB 8691. Leuk Lymphoma. 2009 Oct;50(10):1606-17. link to original article link to PMC article PubMed

G-CVP

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G-CVP: Gazyva (Obinutuzumab), Cyclophosphamide, Vincristine, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2017 (GALLIUM) Phase III (E) See link See link See link

Note: Patients received obinutuzumab only in cycles 7 & 8.

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment

References

  1. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed

G-CHOP

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G-CHOP: Gazyva (Obinutuzumab), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2017 (GALLIUM) Phase III (E) See link See link See link

Note: Patients received obinutuzumab only in cycles 7 & 8.

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment

References

  1. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed

Lenalidomide & Rituximab

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R2: Rituximab & Revlimid (Lenalidomide)

Variant #1

Study Evidence Comparator Comparative Efficacy
Zucca et al. 2019 (SAKK 35/10) Randomized Phase II (E) Rituximab Might 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) as follows:
    • Cycles 1 & 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

Variant #2

Study Evidence
Fowler et al. 2014 Phase II

Chemotherapy

28-day cycle for up to 12 cycles

Variant #3

Study Evidence
Martin et al. 2017 (CALGB 50803) Phase II

Chemotherapy

28-day cycle for 12 cycles

Variant #4

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Morschhauser et al. 2018 (RELEVANCE) Phase III (E) 1. R-B
2. R-CHOP
3. R-CVP
Seems not superior Different toxicity

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. 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 link to PMC article PubMed
  2. SAKK 35/10: Zucca E, Rondeau S, Vanazzi A, Østenstad B, Mey UJM, Rauch D, Wahlin BE, Hitz F, Hernberg M, Johansson AS, de Nully Brown P, Hagberg H, Ferreri AJM, Lohri A, Novak U, Zander T, Bersvendsen H, Bargetzi M, Mingrone W, Krasniqi F, Dirnhofer S, Hayoz S, Hawle H, Vilei SB, Ghielmini M, Kimby E; Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy. Blood. 2019 Jul 25;134(4):353-362. Epub 2019 May 17. link to original article PubMed
  3. CALGB 50803: Martin P, Jung SH, Pitcher B, Bartlett NL, Blum KA, Shea T, Hsi ED, Ruan J, Smith SE, Leonard JP, Cheson BD. A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol. 2017 Nov 1;28(11):2806-2812. link to original article contains protocol PubMed
  4. RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article contains verified protocol PubMed

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Horning & Rosenberg 1984 Non-randomized
Young et al. 1988 Phase III (E) ProMACE-MOPP, then TNI
Brice et al. 1997 Phase III (E) 1. Interferon alfa
2. Prednimustine
Seems not superior
Ardeshna et al. 2003 Phase III (E) Chlorambucil Seems not superior
Ardeshna et al. 2014 Phase III (C) 1. Rituximab induction Inferior TTNT
2. Rituximab induction, then 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 GV, 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), Predniso(lo)ne

Variant #1, 3 cycles with prednisone 100 mg

Study Evidence
Hainsworth et al. 2005a Phase II
Hainsworth et al. 2009 Phase II

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

Preceding treatment

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

Variant #2, 3 cycles with prednisone 100 mg/m2

Study Evidence
Jacobs et al. 2008 Phase II

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

Subsequent treatment

Variant #3, prednisone 100 mg

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Salles et al. 2010 (PRIMA) Non-randomized portion of RCT
Flinn et al. 2014 (BRIGHT) Phase III (C) BR Inconclusive whether non-inferior
Marcus et al. 2017 (GALLIUM) Phase III (C) See link See link See link
Morschhauser et al. 2018 (RELEVANCE) Phase III (C) Lenalidomide & Rituximab Seems not superior Different toxicity

In PRIMA, initial therapy was investigator's choice. 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. Patients in GALLIUM & RELEVANCE received rituximab only in cycles 7 & 8.

Chemotherapy

Supportive medications

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

Subsequent treatment

Variant #4, prednisone 100 mg/m2

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Hiddemann et al. 2005 (GLSG '00) Phase III (E) CHOP Seems to have superior OS Increased toxicity
Federico et al. 2013 (FOLL05) Phase III (E) 1. R-CVP Seems to have superior PFS
2. R-FM Seems not superior

In FOLL05, PFS was superior to R-CVP but equivalent to R-FM; risk/benefit ratio was better than R-FM. Patients in FOLL05 received a total of 8 doses of rituximab, regardless of the number of CHOP cycles.

Chemotherapy

21-day cycle for 6 to 8 cycles

Variant #5, variant rituximab schedule

Study Evidence Comparator Comparative Efficacy
Czuczman et al. 1999 Phase II
Press et al. 2012 (SWOG S0016) Phase III (C) CHOP, then 131Iodine-Tositumomab Inferior PFS (*)

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. Reported efficacy for SWOG S0016 is based on the 2018 update.

Chemotherapy

21-day cycle for 6 cycles

Variant #6, 4 doses of rituximab

Study Evidence Comparator Comparative Efficacy
Watanabe et al. 2011 (JCOG 0203) Phase III (C) 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

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. 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
  3. GLSG '00: 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
  4. 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
  5. 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 SD article contains verified protocol PubMed
  6. PRIMA: 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. 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
  7. JCOG 0203: 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
    1. Update: Watanabe T, Tobinai K, Wakabayashi M, Morishima Y, Kobayashi H, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Yoshino T, Nawano S, Terauchi T, Hotta T, Nagai H, Tsukasaki K; JCOG0203 Collaborators. Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial. Lancet Haematol. 2018 Nov;5(11):e520-e531. link to original article PubMed
  8. SWOG S0016: 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 link to PMC article PubMed
    1. Update: Shadman M, Li H, Rimsza L, Leonard JP, Kaminski MS, Braziel RM, Spier CM, Gopal AK, Maloney DG, Cheson BD, Dakhil S, LeBlanc M, Smith SM, Fisher RI, Friedberg JW, Press OW. Continued excellent outcomes in previously untreated patients with follicular lymphoma after treatment with CHOP plus rituximab or CHOP plus (131)I-tositumomab: long-term follow-up of phase III randomized study SWOG-S0016. J Clin Oncol. 2018 Mar 1;36(7):697-703. Epub 2018 Jan 22. link to original article PubMed
  9. StiL NHL1: 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; 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
  10. FOLL05: 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: Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, Rusconi C, Tarantino V, Tucci A, Vitolo U, Kovalchuk S, Angelucci E, Pulsoni A, Arcaini L, Angrilli F, Gaidano G, Stelitano C, Bertoldero G, Cascavilla N, Salvi F, Ferreri AJM, Vallisa D, Marcheselli L, Federico M. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018 Mar 1;36(7):689-696. Epub 2017 Nov 2. link to original article PubMed
  11. 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
  12. BRIGHT: 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 link to PMC article PubMed
    1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
  13. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed
  14. RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article contains verified protocol in supplement PubMed

R-CHVP+I

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

Regimen

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

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. FL2000: 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 link to PMC article PubMed

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Variant #1, prednisone 40 mg/m2

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2005 Phase III (E) CVP Superior TTP Similar toxicity
Salles et al. 2010 (PRIMA) Non-randomized portion of RCT
Federico et al. 2013 (FOLL05) Phase III (E) 1. R-CHOP Seems to have inferior PFS See paper
2. R-FM Inferior PFS (*) See paper
Morschhauser et al. 2018 (RELEVANCE) Phase III (C) Lenalidomide & Rituximab Seems not superior Different toxicity

Note: reported efficacy for FOLL05 for comparison marked with (*) is based on the 2017 update.

Chemotherapy

21-day cycle for up to 8 cycles

Subsequent treatment

Variant #2, prednisone 100 mg/day

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Flinn et al. 2014 (BRIGHT) Phase III (C) BR Inconclusive whether non-inferior
Marcus et al. 2017 (GALLIUM) Phase III (C) See link See link See link

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. Patients in GALLIUM received rituximab only in cycles 7 & 8.

Chemotherapy

Supportive medications

21-day cycle for up to 8 cycles

Subsequent treatment

Variant #3, 3 cycles

Study Evidence
Hainsworth et al. 2005a Phase II

Preceding treatment

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

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
  2. 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
  3. PRIMA: 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. 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. FOLL05: 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: Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, Rusconi C, Tarantino V, Tucci A, Vitolo U, Kovalchuk S, Angelucci E, Pulsoni A, Arcaini L, Angrilli F, Gaidano G, Stelitano C, Bertoldero G, Cascavilla N, Salvi F, Ferreri AJM, Vallisa D, Marcheselli L, Federico M. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018 Mar 1;36(7):689-696. Epub 2017 Nov 2. link to original article PubMed
  5. BRIGHT: 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 link to PMC article PubMed
    1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
  6. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed
  7. RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article contains verified protocol in supplement PubMed

R-FM

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

Variant #1, 4 cycles

Study Evidence
Zinzani et al. 2011 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

Subsequent treatment

  • Patients were restaged 2 to 3 weeks after finishing cycle 4. People with at least a partial response (PR), ANC greater than 1500/uL, 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)

Variant #2, 8 cycles

Study Evidence Comparator Comparative Efficacy
Federico et al. 2013 (FOLL05) Phase III (E) 1. R-CHOP Seems not superior
2. R-CVP Superior PFS (*)

Note: risk/benefit ratio was worse than R-CHOP. Reported efficacy for comparison marked with (*) is based on the 2017 update.

Chemotherapy

21-day cycle for 8 cycles

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 90Y-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
  2. FOLL05: 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: Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, Rusconi C, Tarantino V, Tucci A, Vitolo U, Kovalchuk S, Angelucci E, Pulsoni A, Arcaini L, Angrilli F, Gaidano G, Stelitano C, Bertoldero G, Cascavilla N, Salvi F, Ferreri AJM, Vallisa D, Marcheselli L, Federico M. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018 Mar 1;36(7):689-696. Epub 2017 Nov 2. link to original article PubMed

R-FND

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

Regimen

Study Evidence
Vitolo et al. 2013 (ML17638) Non-randomized portion of RCT

Chemotherapy

1-month cycle for 4 cycles

Subsequent treatment

References

  1. ML17638: 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 Comparative Efficacy
Herold et al. 2007 (OSHO-39) Phase III (E) MCP Superior OS

Note: the chlorambucil dose is written in the reference as "3 x 3 mg/m2"; total dose per day is 9 mg/m2.

Chemotherapy

28-day cycle for up to 8 cycles

Subsequent treatment

References

  1. OSHO-39: 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 monotherapy

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Variant #1, 4 doses

Study Evidence Comparator Comparative 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 (E) 1. Observation Superior TTNT
2. Rituximab induction, then 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

Supportive medications

4-week course

Subsequent treatment

Variant #2, 8 doses

Study Evidence Comparator Comparative Efficacy
Kimby et al. 2015 (NLG ML16865) Phase III (C) Rituximab & IFN-α2a Seems not superior
Zucca et al. 2019 (SAKK 35/10) Randomized Phase II (C) Lenalidomide & Rituximab Might have inferior CR/CRu rate

Note: only patients achieving some degree of measurable response in NLG ML16865 proceeded to the 2nd course of rituximab.

Chemotherapy

12-week cycle for 2 cycles

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. SAKK 35/98: 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
  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. ECOG E4402: 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 link to PMC article PubMed
  8. SAKK 35/10: Zucca E, Rondeau S, Vanazzi A, Østenstad B, Mey UJM, Rauch D, Wahlin BE, Hitz F, Hernberg M, Johansson AS, de Nully Brown P, Hagberg H, Ferreri AJM, Lohri A, Novak U, Zander T, Bersvendsen H, Bargetzi M, Mingrone W, Krasniqi F, Dirnhofer S, Hayoz S, Hawle H, Vilei SB, Ghielmini M, Kimby E; Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy. Blood. 2019 Jul 25;134(4):353-362. Epub 2019 May 17. link to original article PubMed
  9. NLG ML16865: 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
    1. Pooled Update: Lockmer S, Østenstad B, Hagberg H, Holte H, Johansson AS, Wahlin BE, Wader KF, Steen CB, Meyer P, Maisenhølder M, Smedby KE, Brown P, Kimby E. Chemotherapy-free initial treatment of advanced indolent lymphoma has durable effect with low toxicity: results from two Nordic Lymphoma Group trials with more than 10 years of follow-up. J Clin Oncol. 2018 Nov 20;36(33):3315-23. Epub 2018 Oct 4. link to original article PubMed
  10. SAKK 35/03: 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 link to PMC article PubMed

Advanced disease, first-line therapy, non-randomized or retrospective data

Bendamustine & Ofatumumab

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Regimen

Study Evidence
Czuczman et al. 2015 (C18083-2048) 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. C18083-2048: 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

FR

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FR: Fludarabine & Rituximab

Regimen

Study Evidence Efficacy
Czuczman et al. 2005 Phase II ORR: 90%

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 monotherapy

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Variant #1

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.

Radioimmunotherapy

8- to 9-day course

Variant #2, fractionated

Study Evidence
Illidge et al. 2013 (FIZZ) 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.

Radioimmunotherapy

8- to 12-week cycle for 2 cycles

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. FIZZ: 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
  3. 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

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 (MDACC 2004-0818) Phase II

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

References

  1. MDACC 2004-0818: 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 link to PMC article PubMed
    1. Update: Khashab T, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Vega F, Kwak LW, Samaniego F. Long-term overall- and progression-free survival after pentostatin, cyclophosphamide and rituximab therapy for indolent non-Hodgkin lymphoma. Br J Haematol. 2019 May;185(4):670-678. Epub 2019 Feb 28. link to original article PubMed

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

Subsequent treatment

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. contains verified protocol link to PMC article 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

Subsequent treatment

References

  1. PRIMA: 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. 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

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VR: Velcade (Bortezomib) & Rituximab

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

Subsequent treatment

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

VR-CHOP

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VR-CHOP: Velcade (Bortezomib) Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne

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

Subsequent treatment

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 link to PMC article PubMed

Consolidation after first-line therapy

Note: consolidation here is defined as any regimen with an intended length of treatment of 12 months or less.

Ibritumomab tiuxetan monotherapy

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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.

Variant #1

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

Preceding treatment

  • First-line therapy (most received CHOP or CVP; some received "CHOP-like", "rituximab combination", "fludarabine combination", or chlorambucil), with PR/CR

Radioimmunotherapy

8-day course

Variant #2

Study Evidence Efficacy
Zinzani et al. 2011 Phase II ORR: 89%

Preceding treatment

Radioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 +/- 1 day (total dose: 500 mg/m2)
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) given 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 over 10 minutes once on day 8
    • Platelet count of 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8

8-day course

Variant #3

Study Evidence
Hainsworth et al. 2009 Phase II

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.

Preceding treatment

Radioimmunotherapy

8-day course

Variant #4

Study Evidence Efficacy
Zinzani et al. 2008 (FLUMIZ) Phase II ORR: 98%

Preceding treatment

Radioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 +/- 1 day (total dose: 500 mg/m2)
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) given 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 over 10 minutes once on day 8
    • Platelet count of 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8

8-day course

Variant #5

Study Evidence Efficacy
Jacobs et al. 2008 Phase II ORR: 89%

Preceding treatment

Radioimmunotherapy

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

Chemotherapy

28-day course

Variant #6

Study Evidence Efficacy
Provencio et al. 2013 Phase II ORR: 93%

To be completed; further details are not available in the abstract.

Preceding treatment

Radioimmunotherapy

References

  1. FLUMIZ: 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. FIT: 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: 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 SD 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 90Y-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

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Hagenbeek et al. 1998 Phase III (C) Interferon alfa Might have inferior TTP
Fisher et al. 2000 (SWOG S8809) Phase III (C) Interferon alfa Seems not superior
Ghielmini et al. 2004 (SAKK 35/98) Phase III (C) Rituximab Seems to have inferior EFS
Morschhauser et al. 2008 (FIT) Phase III (C) Ibritumomab tiuxetan Inferior PFS
Hochster et al. 2009 (ECOG E1496) Phase III (C) Rituximab Inferior PFS
Salles et al. 2010 (PRIMA) Phase III (C) Rituximab Inferior PFS
Vitolo et al. 2013 (ML17638) Phase III (C) Rituximab Seems not superior

No further treatment after induction therapy.

Preceding treatment

  • SAKK 35/98: R x 4
  • FIT: First-line therapy (most received CHOP or CVP; some received "CHOP-like", "rituximab combination", "fludarabine combination", or chlorambucil), with PR/CR
  • ECOG E1496: CVP x 6 to 8
  • PRIMA: R-CHOP or R-CVP or R-FCM
  • ML17638: R-FND x 4

References

  1. Hagenbeek A, Carde P, Meerwaldt JH, Somers R, Thomas J, De Bock R, Raemaekers JM, van Hoof A, De Wolf-Peeters C, van Glabbeke M; European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin's lymphoma. J Clin Oncol. 1998 Jan;16(1):41-7. link to original article PubMed
  2. SWOG S8809: Fisher RI, Dana BW, LeBlanc M, Kjeldsberg C, Forman JD, Unger JM, Balcerzak SP, Gaynor ER, Roy V, Miller T. Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809. J Clin Oncol. 2000 May;18(10):2010-6. link to original article PubMed
  3. SAKK 35/98: 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. FIT: 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: 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
  5. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains verified protocol link to PMC article 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 link to PMC article PubMed
  6. PRIMA: 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. 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
  7. ML17638: 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 monotherapy, abbreviated course

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

Variant #1, 2 doses in 2 weeks

Study Evidence
Hainsworth et al. 2005a Phase II

Counting from the beginning, this is given in weeks 14 & 15.

Preceding treatment

Chemotherapy

14-day course

Variant #2, 4 doses in 4 weeks

Study Evidence
Rambaldi et al. 2002 Phase II
Hainsworth et al. 2002 Phase II
Ladetto et al. 2008 Non-randomized portion of RCT

Preceding treatment

  • Rambaldi et al. 2002 & Ladetto et al. 2008: CHOP x 6
  • Hainsworth et al. 2002: Rituximab
  • Zinzani et al. 2004: CHOP x 6 versus FM x 6

Chemotherapy

Supportive medications

4-week course

Variant #3, 4 doses in 4 months

Study Evidence
Sakai et al. 2015 Phase II

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

Variant #4, 8 doses in 8 months

Study Evidence Comparator Comparative Efficacy
Vitolo et al. 2013 (ML17638) Phase III (E) Observation Seems not superior

Preceding treatment

Chemotherapy

2-month cycle for 4 cycles

Variant #5, 8 doses in 9 months

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

Note: maintenance treatment begins in week 12.

Preceding treatment

Chemotherapy

2-month cycle for 4 cycles

References

  1. 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 contains verified protocol PubMed
  2. 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
  3. SAKK 35/98: 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, 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. 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 contains protocol PubMed
  6. ML17638: 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
  7. 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. contains verified protocol link to PMC article PubMed
  8. SAKK 35/03: 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 link to PMC article PubMed

VR

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VR: Velcade (Bortezomib) & Rituximab

Regimen

Study Evidence
Evens et al. 2014 Phase II

Preceding treatment

Chemotherapy

2-month cycle for 4 cycles

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

Maintenance after first-line therapy

Lenalidomide & Rituximab

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R2: Rituximab & Revlimid (Lenalidomide)

Regimen

Study Evidence
Morschhauser et al. 2018 (RELEVANCE) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

8-week cycle for 12 cycles

References

  1. RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article contains verified protocol PubMed

Obinutuzumab monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2017 (GALLIUM) Phase III (E) See link See link See link

Preceding treatment

Chemotherapy

2-month cycle for 12 cycles

References

  1. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Freedman et al. 2009 Phase III (C) Mitumprotimut-T & GM-CSF Seems to have superior TTP

No active antineoplastic treatment.

Preceding treatment

References

  1. Freedman A, Neelapu SS, Nichols C, Robertson MJ, Djulbegovic B, Winter JN, Bender JF, Gold DP, Ghalie RG, Stewart ME, Esquibel V, Hamlin P. Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J Clin Oncol. 2009 Jun 20;27(18):3036-43. Epub 2009 May 4. link to original article link to PMC article PubMed

Rituximab monotherapy, extended course

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

Variant #1, q8wk cycles

Study Evidence Comparator Comparative Efficacy
Salles et al. 2010 (PRIMA) Phase III (E) Observation Superior PFS
Davies et al. 2017 (SABRINA) Phase III (C) SC Rituximab Similar efficacy

Starts 8 weeks after the last induction treatment.

Preceding treatment

Chemotherapy

8-week cycle for 12 cycles

Variant #2, q6mo cycles

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

Preceding treatment

  • CVP x 6 to 8 cycles

Chemotherapy

6-month cycle for 4 cycles (2 years)

Variant #3

Study Evidence Comparator Comparative Efficacy
Ardeshna et al. 2014 Phase III (E) 1. Observation Superior TTNT
2. Rituximab induction, no maintenance Seems not superior

Preceding treatment

Chemotherapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 13: 375 mg/m2 IV once on day 1

28-day cycle for 1 cycle, then 2-month cycle for 12 cycles

Variant #4

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Rummel et al. 2014 (MAINTAIN) Phase III (C) Rituximab x 4y TBD
Witzens-Harig et al. 2014 (MAXIMA) Non-randomized
Marcus et al. 2017 (GALLIUM) Phase III (C) See link See link See link

Preceding treatment

Chemotherapy

2-month cycle for 12 cycles (2 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. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains verified protocol link to PMC article 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 link to PMC article PubMed
  3. PRIMA: 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. 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. MAXIMA: 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
  7. SABRINA: Davies A, Merli F, Mihaljević B, Mercadal S, Siritanaratkul N, Solal-Céligny P, Boehnke A, Berge C, Genevray M, Zharkov A, Dixon M, Brewster M, Barrett M, MacDonald D. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 Jun;4(6):e272-e282. Epub 2017 May 2. link to original article does not contain protocol PubMed
  8. GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix contains verified protocol in appendix PubMed
    1. Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article PubMed

Rituximab monotherapy, very extended course

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Maintenance regimens of more than two years duration.

Variant #1, 4 years

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

Preceding treatment

Chemotherapy

2-month cycle for 24 cycles (4 years)

Variant #2, 5 years

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

Preceding treatment

Chemotherapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 30: 375 mg/m2 IV once on day 1

2-month cycle for up to 30 cycles (5 years)

Variant #3, indefinite

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

Preceding treatment

Chemotherapy

13-week cycles

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. ECOG E4402: 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 link to PMC article PubMed
  3. SAKK 35/03: 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 link to PMC article PubMed

VR

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VR: Velcade (Bortezomib) & Rituximab

Regimen

Study Evidence
Cohen et al. 2015 Phase II

Preceding treatment

Chemotherapy

6-month cycle for up to 4 cycles (2 years)

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 link to PMC article contains verified protocol PubMed

Relapsed or refractory, randomized data

Bendamustine monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Friedberg et al. 2008 Phase II
Kahl et al. 2010 Phase II
Sehn et al. 2016 (GADOLIN) Phase III (C) Bendamustine & Obinutuzumab Seems to have inferior OS (*)

Note: efficacy in GADOLIN is based on the 2018 update.

Chemotherapy

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 link to PMC article PubMed
  3. GADOLIN: 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
    1. Update: Cheson BD, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson G, Mattiello F, Knapp A, Sehn LH. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-2266. Epub 2018 Mar 27. link to original article PubMed

Bendamustine & Obinutuzumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Sehn et al. 2016 (GADOLIN) Phase III (E) Bendamustine Seems to have superior OS

Note: efficacy is based on the 2018 update.

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

Subsequent treatment

References

  1. GADOLIN: 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
    1. Update: Cheson BD, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson G, Mattiello F, Knapp A, Sehn LH. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-2266. Epub 2018 Mar 27. link to original article PubMed

Bevacizumab & Rituximab

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Regimen

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

Chemotherapy

  • Bevacizumab (Avastin) as follows:
    • Cycle 1: 10 mg/kg IV once per day on days 3 & 15
    • Cycles 2 to 5: 10 mg/kg IV once per day on days 1, 15, 29, 43
  • 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

12-week cycle for 1 cycle, then 2-month cycle for 4 cycles

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

Variant #1, 4 cycles

Study Evidence
Matsumoto et al. 2015 (BRB) Phase II

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

Chemotherapy

28-day cycle for 4 cycles

Variant #2, 4 cycles with rituximab lead-in

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

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

Chemotherapy

  • 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 once per day on days 2 & 3

28-day cycle for 4 cycles (see note)

Variant #3, 6 cycles

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

Chemotherapy

28-day cycle for up to 6 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
  3. 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
  4. 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 monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Witzig et al. 1999 Phase I/II
Witzig et al. 2002a Phase III (E) Rituximab Superior ORR
Witzig et al. 2002b Phase II

Witzig et al. 2002b was intended for patients with rituximab-refractory disease.

Radioimmunotherapy

8-day course

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, 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. 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

Lenalidomide monotherapy

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Variant #1, up to 12 cycles

Study Evidence Comparator Comparative Efficacy
Leonard et al. 2015 (CALGB 50401) Randomized Phase II (E) 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

Variant #2, indefinite

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

Chemotherapy

28-day cycles

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
  2. 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 link to PMC article PubMed

Lenalidomide & Rituximab

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Variant #1, len 10

Study Evidence
Chong et al. 2015 Phase II

Chemotherapy

28-day cycles

Variant #2, len dose escalation 15 -> 25 x 12

Study Evidence Comparator Comparative Efficacy
Leonard et al. 2015 (CALGB 50401) Randomized Phase II (E) 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) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 8, 15, 22, 29

Supportive medications

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

28-day cycle for 12 cycles

Variant #3, len 20 x 2

Study Evidence
Tuscano et al. 2014 Phase II

Chemotherapy

Supportive medications

28-day cycle for 2 cycles

Subsequent treatment

  • Responders: Lenalidomide maintenance
  • 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

Variant #4, len 20 x 12

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
AUGMENT (See note) Phase III (E) Lenalidomide Superior PFS

Note: this study has not yet been published.

Chemotherapy

28-day cycle for 12 cycles

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
  3. 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 link to PMC article PubMed
  4. AUGMENT: CT.gov

Obinutuzumab monotherapy

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Variant #1

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

Chemotherapy

28-day course

Subsequent treatment

Variant #2

Study Evidence
Salles et al. 2012 (GAUGUIN) Phase I/II

Note: Dose here is that recommended by Salles et al. 2013 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

21-day cycle for 8 cycles

References

  1. GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed
    1. Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
    2. Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
    3. Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article contains verified protocol PubMed
  2. GAUSS: 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 link to PMC article PubMed

R-CHOP

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

Variant #1, 3 cycles

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

Dosing details for R-CHOP were not available in the abstract; this is a typical R-CHOP regimen.

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

Variant #2, 6 cycles with prednisone 100 mg

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

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

Variant #3, 6 cycles with prednisone 100 mg/m2

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
  2. EORTC 20981: 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 link to PMC article PubMed
  3. 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-FCM

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R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

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

Chemotherapy

28-day cycle for 4 cycles

Subsequent 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 monotherapy

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Variant #1

Study Evidence Comparator Comparative Efficacy
Hainsworth et al. 2014 Randomized (C) Bevacizumab & Rituximab 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 5: 375 mg/m2 IV once on day 1

12-week cycle for 1 cycle, then 2-month cycle for 4 cycles

Variant #2

Study Evidence Comparator Comparative Efficacy
Maloney et al. 1994 Phase 1, <20 pts
Maloney et al. 1997a Phase II
Maloney et al. 1997b Phase 1, <20 pts
McLaughlin et al. 1998 Phase II
Witzig et al. 2002a Phase III (C) Ibritumomab tiuxetan Inferior ORR
Ghielmini et al. 2004 (SAKK 35/98) Non-randomized portion of RCT
Hainsworth et al. 2005b Non-randomized portion of RCT
Sehn et al. 2015 (GAUSS) Randomized Phase II (C) Obinutuzumab Might have inferior ORR

Note: the phase 1 described by Maloney et al. 1994 did not actually employ this dosing level, but is included here for reference purposes.

Chemotherapy

Supportive medications

4-week course

Subsequent treatment

Variant #3

Study Evidence Comparator Comparative Efficacy
Coiffier et al. 2011 (LYM-3001) Phase III (C) 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

35-day cycle for 6 cycles

Variant #4

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

Preceding treatment

Chemotherapy

4-week course, repeated every progression until treatment failure

References

  1. Phase 1: Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood. 1994 Oct 15;84(8):2457-66. link to original article PubMed
  2. Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997 Sep 15;90(6):2188-95. link to original article contains protocol PubMed
  3. Phase 1: Maloney DG, Grillo-López AJ, Bodkin DJ, White CA, Liles TM, Royston I, Varns C, Rosenberg J, Levy R. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1997 Oct;15(10):3266-74. link to original article PubMed
  4. 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
  5. 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
  6. SAKK 35/98: 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
  7. 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
  8. 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 link to PMC article PubMed
  9. ECOG E4402: 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 link to PMC article PubMed
  10. 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
  11. GAUSS: 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 link to PMC article PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Variant #1

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

Chemotherapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV 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

Variant #2

Study Evidence
Agathocleous et al. 2010 Phase II

Chemotherapy

35-day cycle for up to 6 cycles

Variant #3

Study Evidence
de Vos et al. 2009 Phase II

Chemotherapy

35-day cycle for 3 cycles

Variant #4

Study Evidence
Baiocchi et al. 2011 (OSU-0430) 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.

Subsequent treatment

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. OSU-0430: 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 link to PMC article PubMed
  4. 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 link to PMC article PubMed

Relapsed or refractory, non-randomized or retrospective data

Bortezomib monotherapy

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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

BVR

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BVR: Bendamustine, Velcade (Bortezomib), Rituximab
VBR: Velcade (Bortezomib), Bendamustine, Rituximab

Variant #1, 1.3/90/375

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

Chemotherapy

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

Variant #2, 1.6/90/375

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

Note: 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) as follows, given third:
    • 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 verified protocol link to PMC article PubMed
  2. VERTICAL: 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

Copanlisib monotherapy

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Variant #1, flat dose

FDA-recommended dose
Study Evidence Efficacy
CHRONOS-1 (*) Phase II ORR: 59% (95% CI, 49-68)

Note: this is the FDA-recommended dose and the dose used for most of the patients enrolled in this trial; however, the publication to date only details the weight-based dosing (see below).

Chemotherapy

28-day cycles

Variant #2, weight-based

Study Evidence Efficacy
Dreyling et al. 2017 (CHRONOS-1) Phase II ORR: 59% (95% CI, 49-68)

Chemotherapy

28-day cycles

References

  1. CHRONOS-1: Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, Verhoef G, Linton K, Thieblemont C, Vitolo U, Hiemeyer F, Giurescu M, Garcia-Vargas J, Gorbatchevsky I, Liu L, Koechert K, Peña C, Neves M, Childs BH, Zinzani PL. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017 Sep 1;28(9):2169-2178. link to original article link to PMC article contains verified protocol PubMed

FR

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FR: Fludarabine & Rituximab

Regimen

Study Evidence Efficacy
Czuczman et al. 2005 Phase II ORR: 90%

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

Ibrutinib monotherapy

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Regimen

Study Evidence Efficacy
Bartlett et al. 2017 Phase II ORR: 37.5% (95% CI, 23-54)
Gopal et al. 2018 (DAWN) Phase II ORR: 21% (95% CI, 14-30)

Chemotherapy

28-day cycles

References

  1. Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB, Thye LS, Anderson DM, Krysiak K, Ramirez C, Qi J, Siegel BA, Griffith M, Griffith OL, Gomez F, Fehniger TA. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2018 Jan 11;131(2):182-190. Epub 2017 Oct 26. link to original article contains verified protocol PubMed
  2. DAWN: Gopal AK, Schuster SJ, Fowler NH, Trotman J, Hess G, Hou JZ, Yacoub A, Lill M, Martin P, Vitolo U, Spencer A, Radford J, Jurczak W, Morton J, Caballero D, Deshpande S, Gartenberg GJ, Wang SS, Damle RN, Schaffer M, Balasubramanian S, Vermeulen J, Cheson BD, Salles G. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018 Aug 10;36(23):2405-2412. Epub 2018 May 31. link to original article contains protocol PubMed

Idelalisib monotherapy

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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 indefinitely

References

  1. DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article 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

Inotuzumab ozogamicin monotherapy

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Regimen

Study Evidence
Goy et al. 2016 Phase II

Chemotherapy

28-day cycle for 4 to 8 cycles

References

  1. Goy A, Forero A, Wagner-Johnston N, Christopher Ehmann W, Tsai M, Hatake K, Ananthakrishnan R, Volkert A, Vandendries E, Ogura M. A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy. Br J Haematol. 2016 Aug;174(4):571-81. Epub 2016 Apr 22. link to original article PubMed

Lenalidomide, Dexamethasone, Rituximab

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Regimen

Study Evidence
Ahmadi et al. 2013 Phase II, <20 pts in subgroup

Chemotherapy

28-day cycles

References

  1. Ahmadi T, Chong EA, Gordon A, Aqui NA, Nasta SD, Svoboda J, Mato AR, Schuster SJ. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer. 2014 Jan 15;120(2):222-8. Epub 2013 Oct 7. link to original article contains verified protocol PubMed

Ofatumumab monotherapy

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Regimen

Study Evidence
Hagenbeek et al. 2008 (Hx-CD20-001) Phase I/II
Czucman et al. 2012 (405 Study) Phase II

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

Chemotherapy

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

Supportive medications

28-day cycle for 2 cycles

References

  1. Hx-CD20-001: 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. 405 Study: 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 Retrospective

Chemotherapy, induction phase

Supportive medications

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

Chemotherapy, 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 count of at least 3 x 109/L; for example, 5 out of 7 days, every other day, once per week, etc.

References

  1. Retrospective: 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

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

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

Dosing details for R-CVP were not available in the abstract; this is a typical R-CVP regimen.

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

References

  1. UK NCRI LG: 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

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

Chemotherapy

3- to 4-week cycle for 2 cycles

Subsequent treatment

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

Study Evidence Comparator Comparative Efficacy
Nastoupil et al. 2017 Randomized (E) FND, then R Seems not superior

Note: although this is the experimental arm of a negative study, the concurrent approach is the standard approach now.

Chemotherapy

28-day cycle for up to 8 cycles

Subsequent treatment

References

  1. Review: 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
  2. Retrospective: 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
  3. 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 link to PMC article contains verified protocol PubMed

R-INO

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R-INO: Rituximab, INOtuzumab ozogamicin

Regimen

Study Evidence Efficacy
Fayad et al. 2013 Phase I/II ORR: 87%

Chemotherapy

28-day cycle for up to 8 cycles

References

  1. Fayad L, Offner F, Smith MR, Verhoef G, Johnson P, Kaufman JL, Rohatiner A, Advani A, Foran J, Hess G, Coiffier B, Czuczman M, Giné E, Durrant S, Kneissl M, Luu KT, Hua SY, Boni J, Vandendries E, Dang NH. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013 Feb 10;31(5):573-83. Epub 2013 Jan 7. link to original article link to PMC article contains verified protocol PubMed

Temsirolimus monotherapy

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Regimen

Study Evidence
Smith et al. 2010 Phase II

Chemotherapy

28-day cycle for at least 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 link to PMC article PubMed

Vorinostat monotherapy

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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

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 link to PMC article 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 link to PMC article PubMed

Vorinostat & Rituximab

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Regimen

Study Evidence
Chen et al. 2015 (CoH 07195) Phase II, <20 patients in this subgroup

Chemotherapy

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

References

  1. CoH 07195: 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 link to PMC article PubMed

VR-CP

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

Regimen

Study Evidence
Craig et al. 2014 (C05012) Phase II

Chemotherapy

Supportive medications

  • Antiviral prophylaxis against VZV recommended for all patients

21-day cycle for 6 cycles

References

  1. C05012: 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 after subsequent lines of therapy

FCR, then allo HSCT

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen

Study Evidence
Khouri et al. 2001 Phase II

Details are best described in Khouri et al. 2008.

Chemotherapy

Immunosuppressive therapy

GVHD prophylaxis

  • Tacrolimus (Prograf) adjusted to level of 5 to 10 ng/mL for 6 months in patients in remission
  • Methotrexate (MTX) as follows:
    • Related donors: 5 mg/m2 IV once per day on days +1, +3, +6
    • Unrelated donors: 5 mg/m2 IV once per day on days +1, +3, +6, +11

Stem cells transfused on day 0

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 link to PMC article 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 link to PMC article PubMed

Ibritumomab tiuxetan monotherapy

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Regimen

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

Preceding treatment

Radioimmunotherapy

8-day course

References

  1. UK NCRI LG: 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

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Ghielmini et al. 2004 (SAKK 35/98) Phase III (C) Rituximab Seems to have inferior EFS
Forstpointner et al. 2004 Phase III (C) Rituximab Seems to have inferior PFS
Van Oers et al. 2006 (EORTC 20981) Phase III (C) Rituximab Seems to have inferior OS
Pettengell et al. 2013 (EBMT Lym-1) Phase III (C) Rituximab Seems to have inferior PFS

No further treatment after second-line therapy.

Preceding treatment

  • SAKK 35/98: R x 4
  • Forstpointner et al. 2004: R-FCM x 4 versus FCM x 4
  • EORTC 20981: CHOP versus R-CHOP
  • EBMT Lym-1: BEAM with auto HSCT

References

  1. SAKK 35/98: 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. EORTC 20981: 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 link to PMC article PubMed
  4. EBMT Lym-1: Pettengell R, Schmitz N, Gisselbrecht C, Smith G, Patton WN, Metzner B, Caballero D, Tilly H, Walewski JA, Bence-Bruckler I, To B, Geisler CH, Schots R, Kimby E, Taverna CJ, Kozák T, Dreger P, Uddin R, Ruiz de Elvira C, Goldstone AH. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013 May 1;31(13):1624-30. Epub 2013 Apr 1. link to original article PubMed

Rituximab monotherapy, abbreviated course

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

Variant #1, 4 doses

Study Evidence Comparator Comparative Efficacy
Ghielmini et al. 2004 (SAKK 35/98) Phase III (E) Observation Seems to have superior EFS
Pettengell et al. 2013 (EBMT Lym-1) Phase III (E) Observation Seems to have superior EFS

Note: SAKK 35/98 specifies that treatment is to be given at week 12, month 5, 7, 9. Pettengell et al. 2013 does not specify when the maintenance rituximab is to begin post-auto HSCT.

Preceding treatment

Chemotherapy

2-month cycle for 4 cycles

Variant #2, 8 doses

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

Note: first cycle begins 3 months after completion of salvage therapy.

Preceding treatment

Chemotherapy

6-month cycle for 2 cycles

References

  1. SAKK 35/98: 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. EBMT Lym-1: Pettengell R, Schmitz N, Gisselbrecht C, Smith G, Patton WN, Metzner B, Caballero D, Tilly H, Walewski JA, Bence-Bruckler I, To B, Geisler CH, Schots R, Kimby E, Taverna CJ, Kozák T, Dreger P, Uddin R, Ruiz de Elvira C, Goldstone AH. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013 May 1;31(13):1624-30. Epub 2013 Apr 1. link to original article PubMed

R-BEAM, then auto HSCT

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

Regimen

Study Evidence
Kirschey et al. 2014 Phase II

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

Preceding treatment

Chemotherapy

Stem cells re-infused on day 0

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-TBI/Cy, then auto HSCT

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

Regimen

Study Evidence
Kirschey et al. 2014 Phase II

Preceding treatment

Chemotherapy

Radiotherapy

Stem cells reinfused on day 0

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

Cyclophosphamide & TBI, then auto HSCT

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence Comparator Comparative Efficacy
Schouten et al. 2003 (CUP) Phase III (E) CHOP x 3 Might have superior OS

Chemotherapy

Radiotherapy

References

  1. CUP: Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE, Doorduijn JK, Sydes MR, Kvalheim G. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol. 2003 Nov 1;21(21):3918-27. Epub 2003 Sep 29. link to original article PubMed

(90)YFC, then allo HSCT

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(90)YFC: Ibritumomab tiuxetan, Fludarabine, Cyclophosphamide

Regimen

Study Evidence
Khouri et al. 2001 Non-randomized

Chemoradioimmunotherapy

Immunosuppressive therapy

GVHD prophylaxis

Stem cells transfused on day 0

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 link to PMC article 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 link to PMC article PubMed

Maintenance after subsequent lines of therapy

Lenalidomide monotherapy

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Regimen

Study Evidence
Tuscano et al. 2014 Phase II

Preceding treatment

Chemotherapy

Supportive medications

28-day cycles

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 monotherapy

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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

Preceding treatment

Chemotherapy

2-month cycle for 12 cycles

References

  1. GAUSS: 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 link to PMC article PubMed
  2. GADOLIN: 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
    1. Update: Cheson BD, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson G, Mattiello F, Knapp A, Sehn LH. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-2266. Epub 2018 Mar 27. link to original article PubMed

Rituximab monotherapy, extended course

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

Variant #1, 3-month cycles

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

Preceding treatment

Chemotherapy

3-month cycle for up to 8 cycles (2 years)

Variant #2, 2-month cycles

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

Preceding treatment

Chemotherapy

2-month cycle for up to 12 cycles (2 years)

References

  1. EORTC 20981: 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 link to PMC article 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. GAUSS: 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 link to PMC article PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Regimen

Study Evidence
Baiocchi et al. 2011 (OSU-0430) Phase II, <20 patients reported

Preceding treatment

Chemotherapy

6-month cycle for up to 4 cycles (2 years)

References

  1. OSU-0430: 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 link to PMC article 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.