B-cell lymphoma of mucosa-associated lymphoid tissue

Section editor
	Sanjai Sharma, MD Sequoia Regional Cancer Center Visalia, CA

25 regimens on this page 25 variants on this page

Note: these are regimens specific to extranodal marginal zone lymphomas (EMZL) of mucosa-associated lymphoid tissue ("MALTomas"), please see the main MZL page for other regimens.

Guidelines

EGILS

• 2011: Ruskoné-Fourmestraux et al. EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT

ESMO

• 2020: Zucca et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2013: Dreyling et al. ESMO Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma PubMed
• 2013: Zucca et al. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2009: Zucca et al. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Recommendations for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - B-cell Lymphomas

Gastric MALT lymphoma, H. Pylori eradication therapy

Amoxicillin & PPI

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Regimen

Study	Evidence
Bayerdörffer et al. 1995	Non-randomized

Antibiotic therapy

• Amoxicillin 750 mg PO three times per day
• Omeprazole (Prilosec) 40 mg PO three times per day

14-day course

References

1. Bayerdörffer E, Neubauer A, Rudolph B, Thiede C, Lehn N, Eidt S, Stolte M; MALT Lymphoma Study Group. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet. 1995 Jun 24;345(8965):1591-4. link to original article PubMed
   1. Update: Neubauer A, Thiede C, Morgner A, Alpen B, Ritter M, Neubauer B, Wündisch T, Ehninger G, Stolte M, Bayerdörffer E. Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst. 1997 Sep 17;89(18):1350-5. link to original article PubMed
   2. Update: Wündisch T, Thiede C, Morgner A, Dempfle A, Günther A, Liu H, Ye H, Du MQ, Kim TD, Bayerdörffer E, Stolte M, Neubauer A. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol. 2005 Nov 1;23(31):8018-24. Epub 2005 Oct 3. link to original article contains protocol PubMed

Amoxicillin, Clarithromycin, PPI, Bismuth

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Regimen

Study	Evidence
Steinbach et al. 1999	Non-randomized

Antibiotic therapy

• Amoxicillin 750 mg PO three times per day on days 1 to 21
• Clarithromycin (Biaxin) 500 mg PO three times per day on days 1 to 21
• Omeprazole (Prilosec) or Lansoprazole (Prevacid)
• Bismuth subsalicylate (Pepto-Bismol)

8-week cycle for 2 cycles

References

1. Steinbach G, Ford R, Glober G, Sample D, Hagemeister FB, Lynch PM, McLaughlin PW, Rodriguez MA, Romaguera JE, Sarris AH, Younes A, Luthra R, Manning JT, Johnson CM, Lahoti S, Shen Y, Lee JE, Winn RJ, Genta RM, Graham DY, Cabanillas FF. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: an uncontrolled trial. Ann Intern Med. 1999 Jul 20;131(2):88-95. link to original article contains protocol PubMed

Ampicillin, Metronidazole, Bismuth

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Regimen

Study	Evidence
Wotherspoon et al. 1993	Pilot

Antibiotic therapy

• Ampicillin
• Metronidazole (Flagyl)
• Tripotassium dicitratobismuthate (De-Noltab)

References

1. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, Isaacson PG. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993 Sep 4;342(8871):575-7. link to original article PubMed

Ampicillin & PPI

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Regimen

Study	Evidence
Wotherspoon et al. 1993	Pilot

Antibiotic therapy

• Ampicillin
• Omeprazole (Prilosec)

References

1. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, Isaacson PG. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993 Sep 4;342(8871):575-7. link to original article PubMed

Clarithromycin, Metronidzole, PPI

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Regimen

Study	Evidence
Bayerdörffer et al. 1995	Non-randomized

This was second-line treatment.

Antibiotic therapy

• Clarithromycin (Biaxin) 250 mg PO twice per day
• Metronidazole (Flagyl) 400 mg PO three times per day
• Omeprazole (Prilosec) 40 mg PO twice per day

10-day course

References

1. Bayerdörffer E, Neubauer A, Rudolph B, Thiede C, Lehn N, Eidt S, Stolte M; MALT Lymphoma Study Group. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet. 1995 Jun 24;345(8965):1591-4. link to original article PubMed
   1. Update: Neubauer A, Thiede C, Morgner A, Alpen B, Ritter M, Neubauer B, Wündisch T, Ehninger G, Stolte M, Bayerdörffer E. Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst. 1997 Sep 17;89(18):1350-5. link to original article PubMed
   2. Update: Wündisch T, Thiede C, Morgner A, Dempfle A, Günther A, Liu H, Ye H, Du MQ, Kim TD, Bayerdörffer E, Stolte M, Neubauer A. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol. 2005 Nov 1;23(31):8018-24. Epub 2005 Oct 3. link to original article contains verified protocol PubMed

Clarithromycin, Tetracycline, PPI, Bismuth

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Regimen

Study	Evidence
Steinbach et al. 1999	Non-randomized

Antibiotic therapy

• Clarithromycin (Biaxin) 500 mg PO three times per day on days 1 to 21
• Tetracycline (Sumycin) 500 mg PO four times per day on days 1 to 21
• Omeprazole (Prilosec) or Lansoprazole (Prevacid)
• Bismuth subsalicylate (Pepto-Bismol)

8-week cycle for 2 cycles

References

1. Steinbach G, Ford R, Glober G, Sample D, Hagemeister FB, Lynch PM, McLaughlin PW, Rodriguez MA, Romaguera JE, Sarris AH, Younes A, Luthra R, Manning JT, Johnson CM, Lahoti S, Shen Y, Lee JE, Winn RJ, Genta RM, Graham DY, Cabanillas FF. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: an uncontrolled trial. Ann Intern Med. 1999 Jul 20;131(2):88-95. link to original article contains protocol PubMed

Metronidazole, Tetracycline, PPI, Bismuth

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Regimen

Study	Evidence
Steinbach et al. 1999	Non-randomized

Antibiotic therapy

• Metronidazole (Flagyl) 500 mg PO three times per day on days 1 to 21
• Tetracycline (Sumycin) 500 mg PO four times per day on days 1 to 21
• Omeprazole (Prilosec) or Lansoprazole (Prevacid)
• Bismuth subsalicylate (Pepto-Bismol)

8-week cycle for 2 cycles

References

1. Steinbach G, Ford R, Glober G, Sample D, Hagemeister FB, Lynch PM, McLaughlin PW, Rodriguez MA, Romaguera JE, Sarris AH, Younes A, Luthra R, Manning JT, Johnson CM, Lahoti S, Shen Y, Lee JE, Winn RJ, Genta RM, Graham DY, Cabanillas FF. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: an uncontrolled trial. Ann Intern Med. 1999 Jul 20;131(2):88-95. link to original article contains protocol PubMed

Ocular adenexal MALT lymphoma, antibiotic therapy

Doxycycline monotherapy

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Regimen

Study	Evidence
Ferreri et al. 2006	Phase II, <20 patients in this subgroup
Ferreri et al. 2012 (IELSG 27)	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 twice per day

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. IELSG 27: 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

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, first-line therapy

Note: This 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 monotherapy

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Regimen

Study	Evidence
Troch et al. 2009	Phase II

Targeted therapy

• 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 link to PMC article PubMed

Bendamustine & Rituximab (BR)

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BR: Bendamustine, Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Salar et al. 2014 (GELTAMO MALT2008-01)	2009-2011	Phase II

Note: treatment in MALT2008-01 was response adapted; patients with CR after 3 cycles received a total of 4 cycles, whereas patients with PR after 3 cycles received a total of 6 cycles.

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2

Targeted therapy

• 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 (see note)

References

1. GELTAMO MALT2008-01: Salar A, Domingo-Domenech E, Panizo C, Nicolás C, Bargay J, Muntañola A, Canales M, Bello JL, Sancho JM, Tomás JF, Rodríguez MJ, Peñalver FJ, Grande C, Sánchez-Blanco JJ, Palomera L, Arranz R, Conde E, García M, García JF, Caballero D, Montalbán C; Grupo Español de Linfomas/Trasplante de Médula Ósea (GELTAMO). First-line response-adapted treatment with the combination of bendamustine and rituximab in patients with mucosa-associated lymphoid tissue lymphoma (MALT2008-01): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2014 Dec;1(3):e104-11. Epub 2014 Nov 19. link to original article contains protocol PubMed NCT01015248
   1. Update: Salar A, Domingo-Domenech E, Panizo C, Nicolás C, Bargay J, Muntañola A, Canales M, Bello JL, Sancho JM, Tomás JF, Rodríguez MJ, Peñalver J, Grande C, Sánchez-Blanco JJ, Palomera L, Arranz R, Conde E, García M, García JF, Caballero D, Montalbán C. Long-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma. Blood. 2017 Oct 12;130(15):1772-1774. Epub 2017 Aug 11. link to original article PubMed

Chlorambucil monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zucca et al. 2013 (IELSG-19)	2003-2005	Phase III (E-de-esc)	1. Chlorambucil & Rituximab	Seems to have inferior PFS (*)
			2. Rituximab	Did not meet primary endpoint of EFS (*)

Note: reported efficacy is based on the 2017 update.

Chemotherapy

• Chlorambucil (Leukeran) 6 mg/m² PO once per day

6-week course

Subsequent treatment

• Patients with SD or better: Chlorambucil consolidation

References

1. IELSG-19: 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 NCT00210353
   1. Update: Zucca E, Conconi A, Martinelli G, Bouabdallah R, Tucci A, Vitolo U, Martelli M, Pettengell R, Salles G, Sebban C, Guillermo AL, Pinotti G, Devizzi L, Morschhauser F, Tilly H, Torri V, Hohaus S, Ferreri AJM, Zachée P, Bosly A, Haioun C, Stelitano C, Bellei M, Ponzoni M, Moreau A, Jack A, Campo E, Mazzucchelli L, Cavalli F, Johnson P, Thieblemont C. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol. 2017 Jun 10;35(17):1905-1912. Epub 2017 Mar 29. link to original article PubMed

Chlorambucil & Rituximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zucca et al. 2013 (IELSG-19)	2003-2005	Phase III (E-esc)	1. Chlorambucil 2. Rituximab	Seems to have superior PFS (*)

Note: reported efficacy is based on the 2017 update.

Chemotherapy

• Chlorambucil (Leukeran) 6 mg/m² PO once per day

Targeted therapy

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

6-week course

Subsequent treatment

• Patients with SD or better: Chlorambucil & rituximab consolidation

References

1. IELSG-19: 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 NCT00210353
   1. Update: Zucca E, Conconi A, Martinelli G, Bouabdallah R, Tucci A, Vitolo U, Martelli M, Pettengell R, Salles G, Sebban C, Guillermo AL, Pinotti G, Devizzi L, Morschhauser F, Tilly H, Torri V, Hohaus S, Ferreri AJM, Zachée P, Bosly A, Haioun C, Stelitano C, Bellei M, Ponzoni M, Moreau A, Jack A, Campo E, Mazzucchelli L, Cavalli F, Johnson P, Thieblemont C. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol. 2017 Jun 10;35(17):1905-1912. Epub 2017 Mar 29. link to original article PubMed

Cladribine monotherapy

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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 per day on days 1 to 5

28-day cycle for 4 to 6 cycles

Dose reductions

• "In case of a persisting nadir of the WBC count less than or equal to 4.0 × 10⁹/L (or ANC less than or equal to 1500/uL) and/or the platelets less than or equal to 100 × 10⁹/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."

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	Years of enrollment	Evidence
Troch et al. 2012	2008-2010	Phase II

Chemotherapy

• Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 4

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Rituximab (Rituxan)
• Antihistamine IV once on day 1, prior to Rituximab (Rituxan)
• One of the following:
  • Ondansetron (Zofran) IV once per day on days 1 to 4, prior to Cladribine (Leustatin)
  • Tropisetron (Navoban) IV once per day on days 1 to 4, prior to 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 link to PMC article PubMed

FR

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FR: Fludarabine & Rituximab

Regimen

Study	Evidence	Efficacy
Salar et al. 2009	Phase II	ORR: 100%

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
  • Patients greater than 70 years old: same dose, but only once per day on days 1 to 3

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

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

28-day cycle for 4 to 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

Lenalidomide monotherapy

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Regimen

Study	Evidence
Kiesewetter et al. 2012 (LEN-MALT)	Phase II, <20 patients reported

Targeted therapy

• 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. LEN-MALT: 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 link to PMC article PubMed

Lenalidomide & Rituximab

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Regimen

Study	Evidence
Kiesewetter et al. 2016 (AGMT MALT-2)	Phase II

Targeted therapy

• 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 cycle for up to 8 to 12 cycles

References

1. AGMT MALT-2: Kiesewetter B, Willenbacher E, Willenbacher W, Egle A, Neumeister P, Voskova D, Mayerhoefer ME, Simonitsch-Klupp I, Melchardt T, Greil R, Raderer M; AGMT Investigators. A phase 2 study of rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma. Blood. 2017 Jan 19;129(3):383-385. Epub 2016 Nov 22. link to original article contains verified protocol PubMed

MCP

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MCP: Mitoxantrone, Chlorambucil, Prednisone

Regimen

Study	Evidence
Wöhrer et al. 2003	Retrospective

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

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV once per day on days 1 & 2
• Chlorambucil (Leukeran) 3 mg/m² PO three times per day on days 1 to 5
• Prednisone (Sterapred) 25 mg/m² PO 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

Rituximab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Conconi et al. 2003 (IELSG 6)	2000-2001	Phase II
Martinelli et al. 2005	NR	Phase II
Zucca et al. 2013 (IELSG-19)	2003-2005	Phase III (E-switch-ooc)	1. Chlorambucil	Did not meet primary endpoint of EFS
			2. Chlorambucil & Rituximab	Seems to have inferior PFS

Targeted therapy

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

Supportive medications

• Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
• Diphenhydramine (Benadryl) 50 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)

4-week 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 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. IELSG-19: 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 NCT00210353
   1. Update: Zucca E, Conconi A, Martinelli G, Bouabdallah R, Tucci A, Vitolo U, Martelli M, Pettengell R, Salles G, Sebban C, Guillermo AL, Pinotti G, Devizzi L, Morschhauser F, Tilly H, Torri V, Hohaus S, Ferreri AJM, Zachée P, Bosly A, Haioun C, Stelitano C, Bellei M, Ponzoni M, Moreau A, Jack A, Campo E, Mazzucchelli L, Cavalli F, Johnson P, Thieblemont C. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol. 2017 Jun 10;35(17):1905-1912. Epub 2017 Mar 29. link to original article PubMed

Consolidation after first-line therapy

Chlorambucil monotherapy

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Regimen

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

Preceding treatment

• 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. IELSG-19: 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 NCT00210353
   1. Update: Zucca E, Conconi A, Martinelli G, Bouabdallah R, Tucci A, Vitolo U, Martelli M, Pettengell R, Salles G, Sebban C, Guillermo AL, Pinotti G, Devizzi L, Morschhauser F, Tilly H, Torri V, Hohaus S, Ferreri AJM, Zachée P, Bosly A, Haioun C, Stelitano C, Bellei M, Ponzoni M, Moreau A, Jack A, Campo E, Mazzucchelli L, Cavalli F, Johnson P, Thieblemont C. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol. 2017 Jun 10;35(17):1905-1912. Epub 2017 Mar 29. link to original article PubMed

Chlorambucil & Rituximab

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Regimen

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

Preceding treatment

• Chlorambucil & Rituximab induction

Chemotherapy

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

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for up to 4 cycles

References

1. IELSG-19: 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 NCT00210353
   1. Update: Zucca E, Conconi A, Martinelli G, Bouabdallah R, Tucci A, Vitolo U, Martelli M, Pettengell R, Salles G, Sebban C, Guillermo AL, Pinotti G, Devizzi L, Morschhauser F, Tilly H, Torri V, Hohaus S, Ferreri AJM, Zachée P, Bosly A, Haioun C, Stelitano C, Bellei M, Ponzoni M, Moreau A, Jack A, Campo E, Mazzucchelli L, Cavalli F, Johnson P, Thieblemont C. Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy. J Clin Oncol. 2017 Jun 10;35(17):1905-1912. Epub 2017 Mar 29. link to original article PubMed

Observation

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hancock et al. 2008 (LY03)	1995-2001	Phase III (C)	Chlorambucil	Did not meet primary endpoint of RR

No further treatment.

Preceding treatment

• H. pylori eradication therapy

References

1. LY03: Hancock BW, Qian W, Linch D, Delchier JC, Smith P, Jakupovic I, Burton C, Souhami R, Wotherspoon A, Copie-Bergman C, Capella C, Traulle C, Levy M, Cortelazzo S, Ferreri AJ, Ambrosetti A, Pinotti G, Martinelli G, Vitolo U, Cavalli F, Gisselbrecht C, Zucca E. Chlorambucil versus observation after anti-Helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial. Br J Haematol. 2009 Feb;144(3):367-75. Epub 2008 Nov 22. link to original article link to PMC article PubMed

Relapsed or refractory, randomized data

Rituximab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Conconi et al. 2003 (IELSG 6)	2000-2001	Phase II
Martinelli et al. 2005	NR	Phase II

Targeted therapy

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

28-day course

References

1. IELSG 6: 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

Relapsed or refractory, non-randomized or retrospective data

Bortezomib monotherapy

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Regimen variant #1, 1.3 mg/m²

Study	Evidence
Conconi et al. 2011	Phase II

Targeted therapy

• 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 variant #2, 1.5 mg/m²

Study	Evidence
Troch et al. 2009 (Velcade-MALT-Lymphoma)	Phase II

Targeted therapy

• 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. Velcade-MALT-Lymphoma: 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 link to PMC article 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. 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

Cladribine & Rituximab

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Regimen

Study	Years of enrollment	Evidence
Troch et al. 2012	2008-2010	Phase II, <20 patients reported

Chemotherapy

• Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 4

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Rituximab (Rituxan)
• Antihistamine IV once on day 1, prior to Rituximab (Rituxan)
• One of the following:
  • Ondansetron (Zofran) IV once per day on days 1 to 4, prior to Cladribine (Leustatin)
  • Tropisetron (Navoban) IV once per day on days 1 to 4, prior to 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 link to PMC article PubMed

Clarithromycin monotherapy

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Regimen

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

Antibiotic therapy

• Clarithromycin (Biaxin) 2000 mg PO once per day on days 1 to 14

21-day cycle for 4 cycles

References

1. HD-K: 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 NCT01516606

Lenalidomide monotherapy

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Regimen

Study	Evidence
Kiesewetter et al. 2012 (LEN-MALT)	Phase II, <20 patients reported

Targeted therapy

• 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. LEN-MALT: 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 link to PMC article PubMed

Prognosis

MALT-IPI (2017)

Risk factors

• Stage III or IV
• Age older than 70 years
• LDH greater than the upper limit of normal

Calculation

• Low risk: zero risk factors present
• Intermediate risk: one risk factor present
• High risk: two or more risk factors present

References

1. Thieblemont C, Cascione L, Conconi A, Kiesewetter B, Raderer M, Gaidano G, Martelli M, Laszlo D, Coiffier B, Lopez Guillermo A, Torri V, Cavalli F, Johnson PW, Zucca E. A MALT lymphoma prognostic index. Blood. 2017 Sep 21;130(12):1409-1417. Epub 2017 Jul 18. 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