Marginal zone lymphoma

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21 regimens on this page 22 variants on this page

Untreated, randomized data

Note: Untreated in this context implies chemotherapy-naive. Some patients in the following studies, especially those with gastric MALT, received H. pylori eradication therapy or radiation prior to chemotherapy.

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence	Comparator	Efficacy
Flinn et al. 2014 (BRIGHT)	Phase III	R-CHOP R-CVP	Equivalent RR

Chemotherapy

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

• Bendamustine 90 mg/m² IV over 30 minutes once on days 1 & 2
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

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. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article contains verified protocol PubMed

Chlorambucil (Leukeran)

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Regimen #1

Study	Evidence	Comparator	Efficacy
Leblond et al. 2012 (WM1)	Phase III	Fludarabine	Decreased PFS

Chemotherapy

• Chlorambucil (Leukeran) 8 mg/m² (6 mg/m² per day if older than 75 years old) PO once per day on days 1 to 10

Supportive medications

• Recommended PCP prophylaxis with one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim SS) 1 tablet PO once per day
  • Pentamidine (Nebupent) 300 mg inhaled once per month

28-day cycle for up to 12 cycles

Regimen #2

Study	Evidence	Comparator	Efficacy
Zucca et al. 2013 (IELSG-19)	Phase III	Chlorambucil & Rituximab Rituximab	Inferior EFS

Chemotherapy

• Chlorambucil (Leukeran) 6 mg/m² PO once per day on days 1 to 42

One course

Patients with stable disease or better proceeded to chlorambucil consolidation.

References

1. Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013 Jan 20;31(3):301-7. Epub 2012 Dec 10. link to original article contains verified protocol PubMed
2. Zucca E, Conconi A, Laszlo D, López-Guillermo A, Bouabdallah R, Coiffier B, Sebban C, Jardin F, Vitolo U, Morschhauser F, Pileri SA, Copie-Bergman C, Campo E, Jack A, Floriani I, Johnson P, Martelli M, Cavalli F, Martinelli G, Thieblemont C. Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study. J Clin Oncol. 2013 Feb 10;31(5):565-72. Epub 2013 Jan 7. link to original article contains verified protocol PubMed
   1. Abstract: Update: E. Zucca, A. Conconi, G. Martinelli, A. Tucci, U. Vitolo, E. Russo, B. Coiffier, H. Ghesquieres, F. Morschhauser, R. Pettengell, G. Pinotti, L. Devizzi, R. Bouabdallah, C. Copie-Bergman, S. Pileri, A. Jack, E. Campo, A. Lopez-Guillermo, P. W. Johnson, C. Thieblemont. CHLORAMBUCIL PLUS RITUXIMAB PRODUCES BETTER EVENTFREE AND PROGRESSION-FREE SURVIVAL IN COMPARISON WITH CHLORAMBUCIL OR RITUXIMAB ALONE IN EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA (MALT LYMPHOMA): FINAL RESULTS OF THE IELSG-19 STUDY. XII INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA Abstract 007 (2013). link to abstract

Chlorambucil & Rituximab

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Regimen

Study	Evidence	Comparator	Efficacy
Zucca et al. 2013 (IELSG-19)	Phase III	Chlorambucil Rituximab	Superior EFS

Chemotherapy

• Chlorambucil (Leukeran) 6 mg/m² PO once per day on days 1 to 42
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

One course

Patients with stable disease or better proceeded to chlorambucil & rituximab consolidation.

References

1. Zucca E, Conconi A, Laszlo D, López-Guillermo A, Bouabdallah R, Coiffier B, Sebban C, Jardin F, Vitolo U, Morschhauser F, Pileri SA, Copie-Bergman C, Campo E, Jack A, Floriani I, Johnson P, Martelli M, Cavalli F, Martinelli G, Thieblemont C. Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study. J Clin Oncol. 2013 Feb 10;31(5):565-72. Epub 2013 Jan 7. link to original article contains verified protocol PubMed
2. Abstract: E. Zucca, A. Conconi, G. Martinelli, A. Tucci, U. Vitolo, E. Russo, B. Coiffier, H. Ghesquieres, F. Morschhauser, R. Pettengell, G. Pinotti, L. Devizzi, R. Bouabdallah, C. Copie-Bergman, S. Pileri, A. Jack, E. Campo, A. Lopez-Guillermo, P. W. Johnson, C. Thieblemont. CHLORAMBUCIL PLUS RITUXIMAB PRODUCES BETTER EVENTFREE AND PROGRESSION-FREE SURVIVAL IN COMPARISON WITH CHLORAMBUCIL OR RITUXIMAB ALONE IN EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA (MALT LYMPHOMA): FINAL RESULTS OF THE IELSG-19 STUDY. XII INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA Abstract 007 (2013). link to abstract

Fludarabine (Fludara)

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Regimen

Study	Evidence	Comparator	Efficacy
Leblond et al. 2012 (WM1)	Phase III	Chlorambucil	Increased PFS

Chemotherapy

• Fludarabine (Fludara) 40 mg/m² (30 mg/m² per day if older than 75 years old) PO once per day on days 1 to 5

Supportive medications

• Recommended PCP prophylaxis with one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim SS) 1 tablet PO once per day
  • Pentamidine (Nebupent) 300 mg inhaled once per month
• Herpes zoster prophylaxis with one of the following:
  • Valacyclovir (Valtrex) 500 mg PO once per day
  • Acyclovir (Zovirax) 200 to 400 mg PO BID

28-day cycle for up to 6 cycles

References

1. Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013 Jan 20;31(3):301-7. Epub 2012 Dec 10. link to original article contains verified protocol PubMed

R-CHOP

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

Synonyms: R-CHOP-21, CHOP-R

Structured Concept: C9760 (NCI-T), C0393023 (NCI-MT/UMLS)

Example orders

• Example orders for R-CHOP in lymphoma

Regimen

Study	Evidence	Comparator	Efficacy
Flinn et al. 2014 (BRIGHT)	Phase III, <20 in this arm	BR R-CVP	Equivalent RR

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive medications

• Antiemetics, antipyretics, and antibiotics per local standard of care
• G-CSF "according to the American Society of Clinical Oncology guidelines"

21-day cycle for up to 8 cycles

References

1. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article contains verified protocol PubMed

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Flinn et al. 2014 (BRIGHT)	Phase III, <20 in this arm	BR R-CHOP	Equivalent RR

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 750 mg/m² or 1000 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive medications

• Antiemetics, antipyretics, and antibiotics per local standard of care
• G-CSF "according to the American Society of Clinical Oncology guidelines"

21-day cycle for up to 8 cycles

References

1. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article contains verified protocol PubMed

Rituximab (Rituxan)

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Regimen

Study	Evidence	Comparator
Conconi et al. 2003 (IELSG 6)	Phase II
Martinelli et al. 2005	Phase II
Zucca et al. 2013 (IELSG-19)	Phase III	Chlorambucil Chlorambucil & Rituximab
Williams et al. 2016 (RESORT)	Non-randomized

Chemotherapy

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

Supportive medications

• Acetaminophen (Tylenol) 650 mg PO 30 minutes prior to each dose
• Diphenhydramine (Benadryl) 50 mg PO 30 minutes prior to each dose

4-week course

Patients with PR/CR in RESORT were randomized to indefinite rituximab versus salvage rituximab at time of progression.

References

1. Conconi A, Martinelli G, Thiéblemont C, Ferreri AJ, Devizzi L, Peccatori F, Ponzoni M, Pedrinis E, Dell'Oro S, Pruneri G, Filipazzi V, Dietrich PY, Gianni AM, Coiffier B, Cavalli F, Zucca E. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003 Oct 15;102(8):2741-5. link to orginal article contains verified protocol PubMed content property of HemOnc.org
2. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol. 2005 Mar 20;23(9):1979-83. link to original article contains verified protocol PubMed
3. Abstract: E. Zucca, A. Conconi, G. Martinelli, A. Tucci, U. Vitolo, E. Russo, B. Coiffier, H. Ghesquieres, F. Morschhauser, R. Pettengell, G. Pinotti, L. Devizzi, R. Bouabdallah, C. Copie-Bergman, S. Pileri, A. Jack, E. Campo, A. Lopez-Guillermo, P. W. Johnson, C. Thieblemont. CHLORAMBUCIL PLUS RITUXIMAB PRODUCES BETTER EVENTFREE AND PROGRESSION-FREE SURVIVAL IN COMPARISON WITH CHLORAMBUCIL OR RITUXIMAB ALONE IN EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA (MALT LYMPHOMA): FINAL RESULTS OF THE IELSG-19 STUDY. XII INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA Abstract 007 (2013). link to abstract
4. Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol PubMed

Untreated, non-randomized or retrospective data

Note: Untreated in this context implies chemotherapy-naive. Some patients in the following studies, especially those with gastric MALT, received H. pylori eradication therapy or radiation prior to chemotherapy.

Bortezomib (Velcade)

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Regimen

Study	Evidence
Troch et al. 2009	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.5 mg/m² IV bolus once per day on days 1, 4, 8, 11

Supportive medications

• 5-HT3 antagonist IV immediately before Bortezomib (Velcade)
• 500 mL NS after Bortezomib (Velcade)

21-day cycle for up to 8 cycles

References

1. Troch M, Jonak C, Müllauer L, Püspök A, Formanek M, Hauff W, Zielinski CC, Chott A, Raderer M. A phase II study of bortezomib in patients with MALT lymphoma. Haematologica. 2009 May;94(5):738-42. Epub 2009 Mar 31. link to original article contains verified protocol PubMed

Cladribine (Leustatin)

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Regimen

Study	Evidence
Jäger et al. 2002	Phase II

Chemotherapy

• Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once on days 1 to 5

Dose reductions:

• "In case of a persisting nadir of the WBCs = 4.0 × 10^9/L (or neutrophils = 1.5 × 10^9/L) and/or the platelets = 100 × 10^9/L, the next treatment cycle was delayed by 1 week until achieving normal values and then treatment was administered at a reduced dose of 0.1 mg/kg body weight."

Supportive medications

• Not described

28-day cycle for 4 to 6 cycles

References

1. Jäger G, Neumeister P, Brezinschek R, Hinterleitner T, Fiebiger W, Penz M, Neumann HJ, Mlineritsch B, DeSantis M, Quehenberger F, Chott A, Beham-Schmid C, Höfler G, Linkesch W, Raderer M. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study. J Clin Oncol. 2002 Sep 15;20(18):3872-7. link to original article contains verified protocol PubMed

Cladribine & Rituximab

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Regimen

Study	Evidence
Troch et al. 2012	Phase II

Chemotherapy

• Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 4
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO prior to Rituximab (Rituxan)
• Antihistamine IV prior to Rituximab (Rituxan)
• Either Ondansetron (Zofran) or Tropisetron (Navoban) IV immediately before Cladribine (Leustatin)

21-day cycle for up to 6 cycles

References

1. Troch M, Kiesewetter B, Willenbacher W, Willenbacher E, Zebisch A, Linkesch W, Fridrik M, Müllauer L, Greil R, Raderer M. Rituximab plus subcutaneous cladribine in patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a phase II study by the Arbeitsgemeinschaft Medikamentose Tumortherapie. Haematologica. 2013 Feb;98(2):264-8. Epub 2012 Sep 14. link to original article contains verified protocol PubMed

Doxycycline

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Regimen

Study	Evidence
Ferreri et al. 2006	Phase II, <20 patients in this subgroup
Ferreri et al. 2012	Phase II

This treatment was intended for patients with ocular adnexal marginal zone lymphoma (OAMZL), given the association with Chlamydia psittaci.

Antibiotic therapy

• Doxycycline 100 mg PO BID

3-week course

References

1. Ferreri AJ, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, Demeter J, Zallio F, Palmas A, Muti G, Dognini GP, Pasini E, Lettini AA, Sacchetti F, De Conciliis C, Doglioni C, Dolcetti R. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst. 2006 Oct 4;98(19):1375-82. link to original article contains verified protocol PubMed
2. Ferreri AJ, Govi S, Pasini E, Mappa S, Bertoni F, Zaja F, Montalbán C, Stelitano C, Cabrera ME, Giordano Resti A, Politi LS, Doglioni C, Cavalli F, Zucca E, Ponzoni M, Dolcetti R. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J Clin Oncol. 2012 Aug 20;30(24):2988-94. Epub 2012 Jul 16. Erratum in: J Clin Oncol. 2012 Nov 1;30(31):3903. link to original article contains verified protocol PubMed

Fludarabine & Rituximab

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Regimen

Study	Evidence
Salar et al. 2009	Phase II

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV (or 40 mg/m² PO) once per day on days 1 to 5
  • Patients with gastric lymphoma received the cycle 1 dose intravenously to guarantee drug absorption
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Dose reductions:

• • Patients >70 years old could receive Fludarabine (Fludara) at the above dose, but only once per day on days 1 to 3

Supportive medications

• Trimethoprim/Sulfamethoxazole prophylaxis (dose/schedule not listed) per physician preference
• No routine antiviral prophylaxis or G-CSF use

28-day cycles for 4-6 cycles

References

1. Salar A, Domingo-Domenech E, Estany C, Canales MA, Gallardo F, Servitje O, Fraile G, Montalbán C. Combination therapy with rituximab and intravenous or oral fludarabine in the first-line, systemic treatment of patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type. Cancer. 2009 Nov 15;115(22):5210-7. link to orginal article contains verified protocol PubMed

Ibritumomab tiuxetan (Zevalin)

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Regimen

Study	Evidence
Samaniego et al. 2014	Phase II, <20 patients reported
Lossos et al. 2014	Phase II, <20 patients reported

Chemotherapy

• Rituximab (Rituxan) 250 mg/m² IV once on day 1, then another single dose on day 8
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg (maximum dose of 1184 MBq) IV once on day 8, given after Rituximab (Rituxan)

Dose reductions:

• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 11.1 MBq/kg (maximum dose of 1184 MBq) for platelet count between 100 and 149.

One course of therapy

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
2. Lossos IS, Fabregas JC, Koru-Sengul T, Miao F, Goodman D, Serafini AN, Hosein PJ, Stefanovic A, Rosenblatt JD, Hoffman JE. Phase II study of (90)Y Ibritumomab tiuxetan (Zevalin) in patients with previously untreated marginal zone lymphoma. Leuk Lymphoma. 2015 Jun;56(6):1750-5. Epub 2014 Nov 20. link to original article PubMed

Lenalidomide (Revlimid)

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Regimen

Study	Evidence
Kiesewetter et al. 2012	Phase II, <20 patients reported

Chemotherapy

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

Supportive medications

• Aspirin 100 mg PO once per day

28-day cycle for up to 6 cycles

References

1. Kiesewetter B, Troch M, Dolak W, Müllauer L, Lukas J, Zielinski CC, Raderer M. A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma). Haematologica. 2013 Mar;98(3):353-6. Epub 2012 Aug 16. link to orginal article contains verified protocol PubMed

Lenalidomide & Rituximab

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Regimen

Study	Evidence
Fowler et al. 2014	Phase II

Chemotherapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycles up to 12 cycles

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 PubMed

MCP

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MCP: Mitoxantrone, Chlorambucil, Prednisolone

Regimen

Study	Evidence
Wöhrer et al. 2003	Retrospective

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV once per day on days 1 & 2
• Chlorambucil (Leukeran) 3 mg/m² PO TID (written in the reference as "3 x 3 mg/m2"; total dose per day is 9 mg/m2) on days 1 to 5
• Prednisolone (Millipred) 25 mg/m² PO/IV once per day on days 1 to 5

28-day cycle for up to 8 cycles

References

1. Retrospective: Wöhrer S, Drach J, Hejna M, Scheithauer W, Dirisamer A, Püspök A, Chott A, Raderer M. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP). Ann Oncol. 2003 Dec;14(12):1758-61. link to orginal article contains verified protocol PubMed

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

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

Chemotherapy

• Pentostatin (Nipent) 4 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Ondansetron (Zofran) 8 mg (route not specified) prior to chemo
• Diphenhydramine (Benadryl) 25 mg (route not specified) prior to chemo
• 500 ml of 5% dextrose/one-half normal saline before and after each pentostatin dose
• Filgrastim (Neupogen) at the discretion of the treating physician
• Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15 of cycle 1
• Trimethoprim/Sulfamethoxazole (Bactrim DS) once per day three days per week during and for 1 month following therapy
• Acyclovir (Zovirax) 400 mg PO BID during and for 1 month following therapy

21-day cycle for 6 cycles

References

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

Consolidation after upfront therapy

Chlorambucil (Leukeran)

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Regimen

Study	Evidence
Zucca et al. 2013 (IELSG-19)	Non-randomized

Treatment preceded by chlorambucil induction.

Chemotherapy

• Chlorambucil (Leukeran) 6 mg/m² PO once per day on days 1 to 14

28-day cycle for up to 4 cycles

References

1. Zucca E, Conconi A, Laszlo D, López-Guillermo A, Bouabdallah R, Coiffier B, Sebban C, Jardin F, Vitolo U, Morschhauser F, Pileri SA, Copie-Bergman C, Campo E, Jack A, Floriani I, Johnson P, Martelli M, Cavalli F, Martinelli G, Thieblemont C. Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study. J Clin Oncol. 2013 Feb 10;31(5):565-72. Epub 2013 Jan 7. link to original article contains verified protocol PubMed

Chlorambucil & Rituximab

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Regimen

Study	Evidence
Zucca et al. 2013 (IELSG-19)	Non-randomized

Treatment preceded by chlorambucil & rituximab induction.

Chemotherapy

• Chlorambucil (Leukeran) 6 mg/m² PO once per day on days 1 to 14
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for up to 4 cycles

References

1. Zucca E, Conconi A, Laszlo D, López-Guillermo A, Bouabdallah R, Coiffier B, Sebban C, Jardin F, Vitolo U, Morschhauser F, Pileri SA, Copie-Bergman C, Campo E, Jack A, Floriani I, Johnson P, Martelli M, Cavalli F, Martinelli G, Thieblemont C. Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study. J Clin Oncol. 2013 Feb 10;31(5):565-72. Epub 2013 Jan 7. link to original article contains verified protocol PubMed

Rituximab (Rituxan)

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Regimen

Study	Evidence	Comparator	Efficacy
Williams et al. 2016 (RESORT)	Phase III	Salvage rituximab	Seems to have superior TTTF

Treatment preceded by rituximab.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once every 13 weeks

Continued until treatment failure

References

1. Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol PubMed

Relapsed/refractory, non-randomized or retrospective data

Bendamustine

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Regimen

Study	Evidence
Kahl et al. 2010	Phase II, <20 patients reported

Chemotherapy

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

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

21-day cycle for 6 to 8 cycles

References

1. Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Cancer. 2010 Jan 1;116(1):106-14. link to original article contains verified protocol PubMed

Bortezomib (Velcade)

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Regimen #1

Study	Evidence
Conconi et al. 2011	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11

Supportive medications

• No routine growth factors, antibiotic, or antiviral prophylaxis was given

21-day cycle for up to 6 cycles

Regimen #2

Study	Evidence
Troch et al. 2009	Phase II

• Bortezomib (Velcade) 1.5 mg/m² IV bolus once per day on days 1, 4, 8, 11

Supportive medications

• 5-HT3 antagonist IV immediately before Bortezomib (Velcade)
• 500 mL NS after Bortezomib (Velcade)

21-day cycle for up to 8 cycles

References

1. Troch M, Jonak C, Müllauer L, Püspök A, Formanek M, Hauff W, Zielinski CC, Chott A, Raderer M. A phase II study of bortezomib in patients with MALT lymphoma. Haematologica. 2009 May;94(5):738-42. Epub 2009 Mar 31. link to original article contains verified protocol PubMed
2. Conconi A, Martinelli G, Lopez-Guillermo A, Zinzani PL, Ferreri AJ, Rigacci L, Devizzi L, Vitolo U, Luminari S, Cavalli F, Zucca E; International Extranodal Lymphoma Study Group (IELSG). Clinical activity of bortezomib in relapsed/refractory MALT lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group (IELSG). Ann Oncol. 2011 Mar;22(3):689-95. link to original article contains verified protocol PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence
Rummel et al. 2005	Phase II, <20 patients in this subgroup

Chemotherapy

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

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

28-day cycle for 4 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

Cladribine & Rituximab

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Regimen

Study	Evidence
Troch et al. 2012	Phase II, <20 patients reported

Chemotherapy

• Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 4
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO prior to Rituximab (Rituxan)
• Antihistamine IV prior to Rituximab (Rituxan)
• Either Ondansetron (Zofran) or Tropisetron (Navoban) IV immediately before Cladribine (Leustatin)

21-day cycle for up to 6 cycles

References

1. Troch M, Kiesewetter B, Willenbacher W, Willenbacher E, Zebisch A, Linkesch W, Fridrik M, Müllauer L, Greil R, Raderer M. Rituximab plus subcutaneous cladribine in patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a phase II study by the Arbeitsgemeinschaft Medikamentose Tumortherapie. Haematologica. 2013 Feb;98(2):264-8. Epub 2012 Sep 14. link to original article contains verified protocol PubMed

Clarithromycin (Biaxin)

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Regimen

Study	Evidence
Ferreri et al. 2015 (HD-K)	Phase II

Antibiotic therapy

• Clarithromycin (Biaxin) 2 g PO once per day on days 1 to 14

21-day cycle for 4 cycles

References

1. Ferreri AJ, Sassone M, Kiesewetter B, Govi S, Scarfò L, Donadoni G, Raderer M. High-dose clarithromycin is an active monotherapy for patients with relapsed/refractory extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT): the HD-K phase II trial. Ann Oncol. 2015 Aug;26(8):1760-5. Epub 2015 May 1. link to original article contains verified protocol PubMed

Doxycycline

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Regimen

Study	Evidence
Ferreri et al. 2006	Phase II, <20 patients in this subgroup

This treatment was intended for patients with ocular adnexal marginal zone lymphoma (OAMZL), given the association with Chlamydia psittaci.

Antibiotic therapy

• Doxycycline 100 mg PO BID

3-week course

References

1. Ferreri AJ, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, Demeter J, Zallio F, Palmas A, Muti G, Dognini GP, Pasini E, Lettini AA, Sacchetti F, De Conciliis C, Doglioni C, Dolcetti R. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst. 2006 Oct 4;98(19):1375-82. link to original article contains verified protocol PubMed

Idelalisib (Zydelig)

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

Regimen,

Study	Evidence
Gopal et al. 2014 (DELTA)	Phase II, <20 patients in this subgroup

Chemotherapy

• Idelalisib (Zydelig) 150 mg PO BID

Continued until progression, death, or unacceptable toxicity

References

1. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma. N Engl J Med. 2014 Jan 22. link to original article contains verified protocol PubMed
   1. Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708 link to abstract

Lenalidomide (Revlimid)

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Regimen

Study	Evidence
Kiesewetter et al. 2012	Phase II, <20 patients reported

Chemotherapy

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

Supportive medications

• Aspirin 100 mg PO once per day

28-day cycle for up to 6 cycles

References

1. Kiesewetter B, Troch M, Dolak W, Müllauer L, Lukas J, Zielinski CC, Raderer M. A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma). Haematologica. 2013 Mar;98(3):353-6. Epub 2012 Aug 16. link to orginal article contains verified protocol PubMed

Rituximab (Rituxan)

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Regimen

Study	Evidence	Comparator	Efficacy
Conconi et al. 2003	Phase II
Martinelli et al. 2005	Phase II
Williams et al. 2016 (RESORT)	Phase III	Maintenance rituximab	Seems to have inferior TTTF

Treatment in RESORT was preceded by rituximab and is given at time of progression.

Chemotherapy

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

One course

References

1. Conconi A, Martinelli G, Thiéblemont C, Ferreri AJ, Devizzi L, Peccatori F, Ponzoni M, Pedrinis E, Dell'Oro S, Pruneri G, Filipazzi V, Dietrich PY, Gianni AM, Coiffier B, Cavalli F, Zucca E. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003 Oct 15;102(8):2741-5. link to orginal article contains protocol PubMed
2. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol. 2005 Mar 20;23(9):1979-83. link to original article contains protocol PubMed
3. Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol PubMed

Vorinostat (Zolinza)

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Regimen

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

Chemotherapy

• Vorinostat (Zolinza) 200 mg PO BID on days 1 to 14

21-day cycles until progression or unacceptable toxicity

References

1. Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, Matsuoka D, Pulone B, Rotter AJ, Espinoza-Delgado I, Nademanee A, Forman SJ, Gandara D, Newman E. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2011 Mar 20;29(9):1198-203. Epub 2011 Feb 7. link to original article contains verified protocol PubMed

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