Revision as of 01:49, 9 December 2021

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

39 regimens on this page 48 variants on this page

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Guidelines

EMN

2018: Gavriatopoulou et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias PubMed

ESMO

2018: Kastritis et al. Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

2013: Buske et al. Waldenström's macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

"How I Treat"

2019: Dimopoulos MA, Kastritis E. How I treat Waldenström macroglobulinemia. Blood. 2019 Dec 5;134(23):2022-2035. link to original article PubMed

IWWM

Current

2020: Castillo et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia

Older

2016: Leblond et al. Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia
2014: Dimopoulos et al. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus PubMed
2009: Dimopoulos et al. Update on treatment recommendations from the Fourth International Workshop on Waldenström's Macroglobulinemia PubMed
2006: Treon et al. Update on treatment recommendations from the Third International Workshop on Waldenström's Macroglobulinemia PubMed

NCCN

NCCN Guidelines - Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma

First-line therapy, randomized data

Bendamustine & Rituximab (BR)

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BR: Bendamustine, Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008	Phase III, <20 pts in this subgroup (E-switch-ic)	R-CHOP	Superior PFS
Rummel et al. 2012 (MAINTAIN)	2009-2012	Non-randomized

Note: efficacy for StiL NHL1 is for the overall group of patients, of which less than 20 were diagnosed with WM.

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 6 cycles; StiL NHL1 gave 2 additional cycles of rituximab only

Subsequent treatment

MAINTAIN: Observation versus rituximab maintenance

References

Abstract: Rummel, Mathias J., Lerchenmuller, Christian, Greil, Richard, Gorner, Martin, Hensel, Manfred, Engel, Erik, Jaeger, Ulrich, Breuer, Friedhelm, Hertenstein, Bernd, Prummer, Otto, Buske, Christian, Barth, Juergen, Burchardt, Alexander C., Brugger, Wolfram. Bendamustin-Rituximab Induction Followed by Observation or Rituximab Maintenance for Newly Diagnosed Patients with Waldenstrom's Macroglobulinemia: Results From a Prospective, Randomized, Multicenter Study (StiL NHL 7-2008 -MAINTAIN-; ClinicalTrials.gov Identifier: NCT00877214). ASH Annual Meeting Abstracts 2012 120: 2739 link to abstract NCT00877214
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. 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 NCT00991211
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. ASH Annual Meeting 2014, Abstract 4407 link to abstract

Chlorambucil monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Leblond et al. 2012 (WM1)	2001-2009	Phase III (E-switch-ic)	Fludarabine	Inferior OS

This regimen was intended for patients greater than or equal to 18 years old with previously untreated WM and an Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 2.

Chemotherapy

Chlorambucil (Leukeran) as follows:
- Age less than or equal to 75 years: 8 mg/m² PO once per day on days 1 to 10
- Age greater than 75 years: 6 mg/m² 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

References

WM1: 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 NCT00566332; NCT00608374

Fludarabine monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Leblond et al. 2012 (WM1)	2001-2009	Phase III (E-switch-ic)	Chlorambucil	Superior OS

This regimen was intended for patients greater than or equal to 18 years old with previously untreated WM and an Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 2.

Chemotherapy

Fludarabine (Fludara) as follows:
- Age less than or equal to 75 years: 40 mg/m² PO once per day on days 1 to 5
- Age greater than 75 years: 30 mg/m² 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
Varicella zoster (shingles) prophylaxis with ONE of the following:
- Valacyclovir (Valtrex) 500 mg PO once per day
- Acyclovir (Zovirax) 200 to 400 mg PO twice per day

28-day cycle for up to 6 cycles

References

WM1: 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 NCT00566332; NCT00608374

Ibrutinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Treon et al. 2018 (DFCI 15-359)	2016	Phase II
Tam et al. 2020 (ASPEN)	2017-2018	Phase III (C)	Zanubrutinib	Did not meet primary endpoint of CR/VGPR rate

Targeted therapy

Ibrutinib (Imbruvica) 420 mg PO once per day

28-day cycles

References

DFCI 15-359: Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, Demos M, Kofides A, Tsakmaklis N, Chen JG, Munshi M, Chan G, Dubeau T, Raje N, Yee A, O'Donnell E, Hunter ZR, Castillo JJ. Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol. 2018 Sep 20;36(27):2755-2761. Epub 2018 Jul 25. link to original article contains protocol PubMed NCT02604511
ASPEN: Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020 Oct 29;136(18):2038-2050. link to original article contains verified protocol PubMed NCT03053440

Ibrutinib & Rituximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase III (E-RT-esc)	Rituximab	Superior PFS

Targeted therapy

Ibrutinib (Imbruvica) 420 mg PO once per day
Rituximab (Rituxan) as follows:
- Cycles 1 & 5: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article contains verified protocol PubMed NCT02165397

Rituximab monotherapy

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Regimen variant #1, single course (4 doses)

Study	Years of enrollment	Evidence
Gertz et al. 2004 (ECOG E3A98)	NR in abstract	Phase II

Targeted therapy

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

4-week course

Regimen variant #2, "extended" course (8 doses)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2002	1999-2001	Phase II
Dimopoulos et al. 2002a	1999-2002	Phase II, <20 pts in subgroup
Treon et al. 2005	NR	Phase II, <20 pts in subgroup
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase III (C)	Ibrutinib & Rituximab	Inferior PFS

Targeted therapy

Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
- Cycle 4 (Treon et al. 2005) or 5 (iNNOVATE): 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 4 to 5 cycles

References

Dimopoulos MA, Zervas C, Zomas A, Kiamouris C, Viniou NA, Grigoraki V, Karkantaris C, Mitsouli C, Gika D, Christakis J, Anagnostopoulos N. Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol. 2002 May 1;20(9):2327-33. link to original article contains protocol PubMed
Dimopoulos MA, Zervas C, Zomas A, Hamilos G, Gika D, Efstathiou E, Panayiotidis P, Vervessou E, Anagnostopoulos N, Christakis J. Extended rituximab therapy for previously untreated patients with Waldenström's macroglobulinemia. Clin Lymphoma. 2002 Dec;3(3):163-6. link to original article contains protocol PubMed
ECOG E3A98: Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004 Oct;45(10):2047-55. link to original article contains protocol PubMed
Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Branagan AR, Anderson KC, Frankel SR; Waldenström's Macroglobulinemia Clinical Trials Group. Extended rituximab therapy in Waldenström's macroglobulinemia. Ann Oncol. 2005 Jan;16(1):132-8. link to original article contains verified protocol PubMed
iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article contains verified protocol PubMed NCT02165397

R-CHOP

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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
R-CHOP-21
CHOP-R

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008	Phase III, <20 pts in this subgroup (C)	BR	Inferior PFS

Note: efficacy for StiL NHL1 is for the overall group of patients, of which less than 20 were diagnosed with WM.

Targeted therapy

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

Chemotherapy

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 IV once on day 1
Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle for up to 6 cycles

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buske et al. 2009	2000-2003	Phase III (E-esc)	CHOP	Superior TTF

Targeted therapy

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

Chemotherapy

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) IV once on day 1
Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 4 to 8 cycles

References

Buske C, Hoster E, Dreyling M, Eimermacher H, Wandt H, Metzner B, Fuchs R, Bittenbring J, Woermann B, Hohloch K, Hess G, Ludwig WD, Schimke J, Schmitz S, Kneba M, Reiser M, Graeven U, Klapper W, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Leukemia. 2009 Jan;23(1):153-61. Epub 2008 Sep 25. link to original article contains verified protocol PubMed
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. 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 NCT00991211
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. ASH Annual Meeting 2014, Abstract 4407 link to abstract

Zanubrutinib monotherapy

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Regimen variant #1

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tam et al. 2020 (ASPEN)	2017-2018	Phase III (E-RT-switch-ic)	Ibrutinib	Did not meet primary endpoint of CR/VGPR rate

Targeted therapy

Zanubrutinib (Brukinsa) 160 mg PO twice per day

28-day cycles

Regimen variant #2

FDA-recommended dose

Note: this is not the dosing that was used in the ASPEN study.

Targeted therapy

Zanubrutinib (Brukinsa) 320 mg PO once per day

28-day cycles

References

ASPEN: Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous JV, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Trotman J, Chan WY, Schneider J, Ro S, Cohen A, Huang J, Dimopoulos M. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020 Oct 29;136(18):2038-2050. link to original article contains verified protocol PubMed NCT03053440

First-line therapy, non-randomized or retrospective data

BDR

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BDR: Bortezomib, Dexamethasone, Rituximab

Regimen variant #1

Study	Evidence
Treon et al. 2009 (WMCTG 05-180)	Phase II

Note: some details are missing in Treon et al. 2009; the updated abstract provides these additional details.

Targeted therapy

Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11
Rituximab (Rituxan) 375 mg/m² IV once on day 11

Chemotherapy

Dexamethasone (Decadron) 40 mg IV once per day on days 1, 4, 8, 11

Supportive medications

Varicella zoster (shingles) prophylaxis with ONE of the following recommended:
- Valacyclovir (Valtrex) 1000 mg PO once per day
- Acyclovir (Zovirax) 400 mg PO twice per day
"The use of diphenhydramine, acetaminophen and, at the treating physician's discretion, corticosteroids and/or ranitidine or cimetidine was permitted for rituximab infusion prophylaxis. Granulocyte colony-stimulating factor, erythropoietin, and transfusions of packed RBCs or platelets were permitted to support patient's counts during therapy."
"The prophylactic use of plasmapheresis was recommended for patients demonstrating an IgM level of greater than or equal to 5000 mg/dL before the administration of Rituximab (Rituxan), given the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity."

21-day cycle for 4 cycles, followed by a 12-week pause and then 4 additional 21-day cycles spaced 12 weeks apart

Regimen variant #2

Study	Evidence
Dimopoulos et al. 2013 (BDR-WM)	Phase II

The schedule for this regimen can be confusing, in particular the first cycle is 21 days and the remaining cycles are 35 days.

Targeted therapy

Bortezomib (Velcade) as follows:
- Cycle 1: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
- Cycles 2 to 5: 1.6 mg/m² IV once per day on days 1, 8, 15, 22
Rituximab (Rituxan) as follows:
- Cycles 2 and 5 only: 375 mg/m² IV once per day on days 1, 8, 15, 22

Chemotherapy

Dexamethasone (Decadron) as follows:
- Cycles 2 and 5 only: 40 mg IV once per day on days 1, 8, 15, 22

Supportive medications

Acetaminophen (Tylenol) 1000 mg PO once per day on days 1, 8, 15, 22, prior to Rituximab (Rituxan)
Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22, prior to Rituximab (Rituxan)
Varicella zoster (shingles) prophylaxis with ONE of the following mandated:
- Valacyclovir (Valtrex) (dose not specified)
- Acyclovir (Zovirax) (dose not specified)

21-day cycle for 1 cycle, then 35-day cycle for 4 cycles

References

WMCTG 05-180: Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M, Willen M, Matous J, Mattern J 2nd, Diener JG, Keogh GP, Myers TJ, Boral A, Birner A, Esseltine DL, Ghobrial IM; WMCTG. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009 Aug 10;27(23):3830-5. Epub 2009 Jun 8. link to original article contains verified protocol link to PMC article PubMed content property of HemOnc.org NCT00250926
1. Update: Abstract: Steven P Treon, Kirsten Meid, Joshua Gustine, Christopher J Patterson, Jeffrey V. Matous, Irene M. Ghobrial, Jorge J Castillo. Long-Term Outcome of a Prospective Study of Bortezomib, Dexamethasone and Rituximab (BDR) in Previously Untreated, Symptomatic Patients with Waldenstrom's Macroglobulinemia. Blood 2015 126:1833. link to abstract
BDR-WM: Dimopoulos MA, García-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Kastritis E, Sonneveld P. Primary therapy of Waldenstrom's macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone and rituximab (BDR): long term results of a phase II study of the European Myeloma Network (EMN). Blood. 2013 Nov 7;122(19):3276-82. Epub 2013 Sep 4. link to original article contains verified protocol PubMed NCT00832234
1. Update: Gavriatopoulou M, García-Sanz R, Kastritis E, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Sonneveld P, Dimopoulos MA. BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years. Blood. 2017 Jan 26;129(4):456-459. link to original article PubMed

CaRD

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CaRD: Carfilzomib, Rituximab, Dexamethasone

Regimen

Study	Evidence
Treon et al. 2014 (DFCI 11-279)	Phase II

Targeted therapy

Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m² IV over 20 minutes once per day on days 1, 2, 8, 9
- Subsequent cycles: 36 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9
Rituximab (Rituxan) 375 mg/m² IV once per day on days 2 & 9, given third

Chemotherapy

Dexamethasone (Decadron) 20 mg IV once per day on days 1, 2, 8, 9

Supportive medications

Acyclovir (Zovirax) 400 mg PO twice per day for duration of therapy and continue for 6 months
Famotidine (Pepcid) 20 mg PO twice per day during active therapy
Dexamethasone (Decadron) 10 mg PO the night before Rituximab (Rituxan) was recommended
Prophylactic plasmapheresis and hold on rituximab was recommended for patients demonstrating an IgM level of greater than or equal to 4000 mg/dL

21-day cycle for 6 cycles

Patients with stable disease or better began CaRD maintenance 8 weeks later.

References

DFCI 11-279: Treon SP, Tripsas CK, Meid K, Kanan S, Sheehy P, Chuma S, Xu L, Cao Y, Yang G, Liu X, Patterson CJ, Warren D, Hunter ZR, Turnbull B, Ghobrial IM, Castillo JJ. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014 Jul 24;124(4):503-10. Epub 2014 May 23. link to original article contains verified protocol PubMed NCT01470196

Cladribine & Rituximab

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Regimen

Study	Evidence
Laszlo et al. 2010	Phase II

Chemotherapy

Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 5

Targeted therapy

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

1-month cycle for 4 cycles

References

Laszlo D, Andreola G, Rigacci L, Fabbri A, Rabascio C, Mancuso P, Pruneri G, Radice D, Pinto A, Frigeri F, Calabrese L, Billio A, Bertolini F, Martinelli G. Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study. J Clin Oncol. 2010 May 1;28(13):2233-8. Epub 2010 Apr 5. link to original article contains verified protocol PubMed IEURONC_*II_204_003

DRC

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DRC: Dexamethasone, Rituximab, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Dimopoulos et al. 2007 (ECWM-1)	2002-2006	Phase II

Note: The body text of Dimopoulos et al 2007 said that the regimen is given for "six courses," whereas the abstract says that it is given for 6 months."

Chemotherapy

Dexamethasone (Decadron) 20 mg IV once on day 1, given first
Cyclophosphamide (Cytoxan) 100 mg/m² PO twice per day on days 1 to 5 (total dose per cycle: 1000 mg/m²)

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once on day 1, given second

21-day cycle for 6 cycles

References

ECWM-1: Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, Repoussis P, Symeonidis A, Delimpasi S, Katodritou E, Vervessou E, Michali E, Pouli A, Gika D, Vassou A, Terpos E, Anagnostopoulos N, Economopoulos T, Pangalis G. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007 Aug 1;25(22):3344-9. link to original article contains verified protocol PubMed NCT01788020
1. Update: Kastritis E, Gavriatopoulou M, Kyrtsonis MC, Roussou M, Hadjiharissi E, Symeonidis A, Repoussis P, Michalis E, Delimpasi S, Tsatalas K, Tsirigotis P, Vassou A, Vervessou E, Katodritou E, Gika D, Terpos E, Dimopoulos MA. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. Blood. 2015 Sep 10;126(11):1392-4. link to original article PubMed

Everolimus monotherapy

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Regimen

Study	Evidence
Treon et al. 2016 (WMCTG 09-214)	Phase II

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day

28-day cycles

References

WMCTG 09-214: Treon SP, Meid K, Tripsas C, Heffner LT, Eradat H, Badros AZ, Xu L, Hunter ZR, Yang G, Patterson CJ, Gustine J, Castillo JJ, Matous J, Ghobrial IM. Prospective, multicenter clinical trial of everolimus as primary therapy in Waldenstrom macroglobulinemia (WMCTG 09-214). Clin Cancer Res. 2017 May 15;23(10):2400-2404. Epub 2016 Nov 11. link to original article contains protocol PubMed NCT00976248

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen

Study	Evidence
Tedeschi et al. 2011	Phase II

Chemotherapy

Fludarabine (Fludara) 25 mg/m² IV once per day on days 2 to 4
Cyclophosphamide (Cytoxan) 250 mg/m² IV once per day on days 2 to 4

Targeted therapy

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

Supportive medications

Diphenhydramine (Benadryl) (dose not specified) IV once on day 1, prior to Rituximab (Rituxan)
Acetaminophen (Tylenol) (dose not specified) PO once on day 1, prior to Rituximab (Rituxan)
Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose not specified) PO three times per week during and for 6 months after treatment
Acyclovir (Zovirax) 800 mg PO once per day during and for 6 months after treatment

28-day cycle for up to 6 cycles

References

Tedeschi A, Benevolo G, Varettoni M, Battista ML, Zinzani PL, Visco C, Meneghini V, Pioltelli P, Sacchi S, Ricci F, Nichelatti M, Zaja F, Lazzarino M, Vitolo U, Morra E. Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer. 2012 Jan 15;118(2):434-43. Epub 2011 Jul 5. link to original article contains verified protocol PubMed

Fludarabine monotherapy

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Regimen

Study	Evidence
Dhodapkar et al. 2001 (SWOG S9003)	Phase II

Chemotherapy

Fludarabine (Fludara) 30 mg/m² PO once per day on days 1 to 5

28-day cycle for 4 to 8 cycles

References

SWOG S9003: Dhodapkar MV, Jacobson JL, Gertz MA, Rivkin SE, Roodman GD, Tuscano JM, Shurafa M, Kyle RA, Crowley JJ, Barlogie B. Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003). Blood. 2001 Jul 1;98(1):41-8. link to original article contains verified protocol PubMed
1. Update: Dhodapkar MV, Jacobson JL, Gertz MA, Crowley JJ, Barlogie B. Prognostic factors and response to fludarabine therapy in Waldenstrom's macroglobulinemia: an update of a US intergroup trial (SW0G S9003). Semin Oncol. 2003 Apr;30(2):220-5. link to original article PubMed
2. Update: Dhodapkar MV, Hoering A, Gertz MA, Rivkin S, Szymonifka J, Crowley J, Barlogie B. Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood. 2009 Jan 22;113(4):793-6. Epub 2008 Oct 17. link to original article link to PMC article PubMed

Fludarabine & Rituximab (FR)

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FR: Fludarabine & Rituximab

Regimen

Study	Years of enrollment	Evidence
Treon et al. 2008 (UCLA-0101063)	2001-2003	Phase II

Chemotherapy

Fludarabine (Fludara) as follows:
- Cycles 2 to 4: 25 mg/m² (route not specified) once per day on days 1 to 5
- Cycles 5 to 7: 25 mg/m² (route not specified) once per day on days 8 to 12

Targeted therapy

Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
- Cycle 5: 375 mg/m² IV once per day on days 1 & 8
- Cycle 8: 375 mg/m² IV once per day on days 15 & 22

28-day cycle for 8 cycles

References

UCLA-0101063: Treon SP, Branagan AR, Ioakimidis L, Soumerai JD, Patterson CJ, Turnbull B, Wasi P, Emmanouilides C, Frankel SR, Lister A, Morel P, Matous J, Gregory SA, Kimby E. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood. 2009 Apr 16;113(16):3673-8. Epub 2008 Nov 17. link to original article contains verified protocol link to PMC article PubMed NCT00020800

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab
PER: Pentostatin, Endoxan (Cyclophosphamide), Rituximab

Regimen

Study	Years of enrollment	Evidence
Herth et al. 2014	2005-2010	Phase II

Chemotherapy

Pentostatin (Nipent) 4 mg/m² IV once on day 2
Cyclophosphamide (Cytoxan) 600 mg/m² (route not specified) on day 2

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once on day 1
- Note: rituximab is not given in cycle 1 if WBC count greater than 50 x 10⁹/L

21-day cycle for 6 cycles

Subsequent treatment

Patients with CR/PR: Rituximab maintenance

References

Herth I, Hensel M, Rieger M, Horstmann K, Hiddemann W, Dreyling M, Koniczek S, Witzens-Harig M, Ho AD. Pentostatin, cyclophosphamide and rituximab is a safe and effective treatment in patients with Waldenström's macroglobulinemia. Leuk Lymphoma. 2015 Jan;56(1):97-102. Epub 2014 Jun 25. link to original article contains verified protocol PubMed

Thalidomide & Rituximab

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Regimen

Study	Evidence
Treon et al. 2008 (DFCI 03-077)	Phase II

Targeted therapy

Thalidomide (Thalomid) as follows:
- Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28
- Cycles 2 to 13: 400 mg PO once per day
Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m² IV once per day on days 8, 15, 22
- Cycle 2: 375 mg/m² IV once on day 1
- Cycle 4: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 13 cycles (1 year)

References

DFCI 03-077: Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, Briccetti FM, Pasmantier M, Zimbler H, Cooper RB, Moore M, Hill J 2nd, Rauch A, Garbo L, Chu L, Chua C, Nantel SH, Lovett DR, Boedeker H, Sonneborn H, Howard J, Musto P, Ciccarelli BT, Hatjiharissi E, Anderson KC. Thalidomide and rituximab in Waldenstrom macroglobulinemia. Blood. 2008 Dec 1;112(12):4452-7. Epub 2008 Aug 19. link to original article contains verified protocol link to PMC article PubMed NCT00142116

Thioguanine monotherapy

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Regimen

Study	Evidence
Weiss et al. 1963	Pilot

Of historic interest.

Chemotherapy

Thioguanine (Tabloid)

References

Weiss CH, Demis DJ, Elgart ML, Brown CS, Crosby WH. Treatment of two cases of hyperglobulinemic purpura with thioguanine. N Engl J Med. 1963 Apr 4;268:753-6. link to original article PubMed

VR

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VR: Velcade (Bortezomib) & Rituximab

Regimen

Study	Evidence
Ghobrial et al. 2010 (DFCI 06-008)	Phase II

Targeted therapy

Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1, 8, 15
Rituximab (Rituxan) as follows:
- Cycles 1 to 4: 375 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

"Antiviral prophylaxis was recommended in all patients prior to initiation of therapy and for 3 months after completion of the six cycles."

28-day cycle for up to 6 cycles

References

DFCI 06-008: Ghobrial IM, Hong F, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1422-8. Epub 2010 Feb 8. link to original article contains verified protocol link to PMC article PubMed NCT00422799
1. Update: Ghobrial IM, Xie W, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Poon T, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia. Am J Hematol. 2010 Sep;85(9):670-4. link to original article contains verified protocol PubMed

Maintenance after first-line therapy

CaRD

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CaRD: Carfilzomib, Rituximab, Dexamethasone

Regimen

Study	Evidence
Treon et al. 2014 (DFCI 11-279)	Phase II

Preceding treatment

CaRD induction x 6 cycles

Targeted therapy

Carfilzomib (Kyprolis) 36 mg/m² IV once per day on days 1 & 2
Rituximab (Rituxan) 375 mg/m² IV once on day 2, given third

Chemotherapy

Dexamethasone (Decadron) 20 mg IV once per day on days 1 & 2

8-week cycle for 8 cycles

References

DFCI 11-279: Treon SP, Tripsas CK, Meid K, Kanan S, Sheehy P, Chuma S, Xu L, Cao Y, Yang G, Liu X, Patterson CJ, Warren D, Hunter ZR, Turnbull B, Ghobrial IM, Castillo JJ. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014 Jul 24;124(4):503-10. Epub 2014 May 23. link to original article contains verified protocol PubMed NCT01470196

Rituximab monotherapy

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Regimen

Study	Years of enrollment	Evidence
Herth et al. 2014	2005-2010	Phase II

Preceding treatment

PER x 6

Targeted therapy

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

3-month cycle for 8 cycles (2 years)

References

Herth I, Hensel M, Rieger M, Horstmann K, Hiddemann W, Dreyling M, Koniczek S, Witzens-Harig M, Ho AD. Pentostatin, cyclophosphamide and rituximab is a safe and effective treatment in patients with Waldenström's macroglobulinemia. Leuk Lymphoma. 2015 Jan;56(1):97-102. Epub 2014 Jun 25. link to original article contains verified protocol PubMed

Relapsed or refractory, randomized data

Bendamustine & Rituximab (BR)

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BR: Bendamustine, Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase III (E-switch-ic)	FR	Seems to have superior OS

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

28-day cycle for up to 6 cycles

References

StiL NHL 2-2003: Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study Group indolent Lymphomas. 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 NCT01456351

Fludarabine & Rituximab (FR)

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FR: Fludarabine & Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase III (C)	BR	Seems to have inferior OS

Chemotherapy

Fludarabine (Fludara) 25 mg/m² (route not specified) once per day on days 1 to 3

Targeted therapy

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

28-day cycle for up to 6 cycles

References

StiL NHL 2-2003: Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study Group indolent Lymphomas. 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 NCT01456351

Ibrutinib & Rituximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase III (E-RT-esc)	Rituximab	Superior PFS

Targeted therapy

Ibrutinib (Imbruvica) 420 mg PO once per day
Rituximab (Rituxan) as follows:
- Cycles 1 & 5: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article contains verified protocol PubMed NCT02165397

Rituximab monotherapy

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Regimen variant #1, single course (4 doses)

Study	Years of enrollment	Evidence
Gertz et al. 2004 (ECOG E3A98)	NR in abstract	Phase II

Targeted therapy

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

4-week course

Regimen variant #2, "extended" course (8 doses)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2002	1999-2001	Phase II
Treon et al. 2005	NR	Phase II, <20 pts in subgroup
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase III (C)	Ibrutinib & Rituximab	Inferior PFS

Targeted therapy

Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
- Cycle 4 (Treon et al. 2005) or 5 (iNNOVATE): 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 4 to 5 cycles

References

Dimopoulos MA, Zervas C, Zomas A, Kiamouris C, Viniou NA, Grigoraki V, Karkantaris C, Mitsouli C, Gika D, Christakis J, Anagnostopoulos N. Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol. 2002 May 1;20(9):2327-33. link to original article contains protocol PubMed
ECOG E3A98: Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004 Oct;45(10):2047-55. link to original article contains protocol PubMed
Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Branagan AR, Anderson KC, Frankel SR; Waldenström's Macroglobulinemia Clinical Trials Group. Extended rituximab therapy in Waldenström's macroglobulinemia. Ann Oncol. 2005 Jan;16(1):132-8. link to original article contains verified protocol PubMed
iNNOVATE: Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. Epub 2018 Jun 1. link to original article contains verified protocol PubMed NCT02165397

Relapsed or refractory, non-randomized or retrospective data

Alemtuzumab monotherapy

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Regimen

Study	Evidence
Hale et al. 1988	Pilot
Treon et al. 2011 (DFCI 02-079)	Phase II

Note: Hale et al. 1998 is the first reported use of this monoclonal antibody and possibly the first clinical trial of monoclonal antibodies in cancer. One of the two patients had lymphoplasmacytoid lymphoma. Per DFCI 02-079, "Alemtuzumab is an active therapy.., but short- and long-term toxicities need to be carefully weighed against other available treatment options."

Targeted therapy

Alemtuzumab (Campath) as follows:
- Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 3, then 30 mg IV once on day 5
- Cycles 2 to 13: 30 mg IV once per day on days 1, 3, 5

Supportive medications

1 L of normal saline prior to Alemtuzumab (Campath)
Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 3, 5, prior to Alemtuzumab (Campath)
Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 3, 5, prior to Alemtuzumab (Campath)
Hydrocortisone (Cortef) 100 to 200 mg IV once per day on days 1, 3, 5, prior to Alemtuzumab (Campath) if patient had a prior reaction
Cimetidine (Tagamet) 300 mg IV once per day on days 1, 3, 5, prior to Alemtuzumab (Campath) if patient had a prior reaction
Famciclovir (Famvir) 250 mg PO twice per day "or the equivalent" during treatment and for 3 months afterwards
Trimethoprim-Sulfamethoxazole (Bactrim DS) PO twice per day three times per week during treatment and for 3 months afterwards
- Dapsone (Aczone) (dose not specified) instead, for patients with sulfur allergy

7-day cycle for 13 cycles

References

Hale G, Dyer MJ, Clark MR, Phillips JM, Marcus R, Riechmann L, Winter G, Waldmann H. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. Lancet. 1988 Dec 17;2(8625):1394-9. link to original article PubMed
DFCI 02-079: Treon SP, Soumerai JD, Hunter ZR, Patterson CJ, Ioakimidis L, Kahl B, Boxer M. Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab. Blood. 2011 Jul 14;118(2):276-81. Epub 2011 May 12. link to original article contains verified protocol link to PMC article PubMed NCT00142181

Bortezomib monotherapy

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Regimen variant #1, 4 cycles

Study	Evidence
Dimopoulos et al. 2005	Phase II, <20 pts

Targeted therapy

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

21-day cycle for 4 cycles

Regimen variant #2, 8 cycles

Study	Evidence
Treon et al. 2007 (WMCTG 03-248)	Phase II

Targeted therapy

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

Up to 8 cycles (cycle duration not defined)

Regimen variant #3, response-adapted

Study	Evidence
Chen et al. 2007 (NCIC-CTG I152)	Phase II

Targeted therapy

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

21-day cycles until PD or 2 cycles past CR or stable PR

References

Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Castritis E, Bitsaktsis A, Pangalis GA. Treatment of relapsed or refractory Waldenström's macroglobulinemia with bortezomib. Haematologica. 2005 Dec;90(12):1655-8. link to original article contains protocol PubMed
NCIC-CTG I152: Chen CI, Kouroukis CT, White D, Voralia M, Stadtmauer E, Stewart AK, Wright JJ, Powers J, Walsh W, Eisenhauer E; National Cancer Institute of Canada Clinical Trials Group. Bortezomib is active in patients with untreated or relapsed Waldenstrom's macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 Apr 20;25(12):1570-5. link to original article contains verified protocol PubMed NCT00045695
WMCTG 03-248: Treon SP, Hunter ZR, Matous J, Joyce RM, Mannion B, Advani R, Cook D, Songer J, Hill J, Kaden BR, Sharon D, Steiss R, Leleu X, Branagan AR, Badros A. Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom's macroglobulinemia: results of WMCTG Trial 03-248. Clin Cancer Res. 2007 Jun 1;13(11):3320-5. link to original article contains verified protocol PubMed

Bendamustine & Rituximab (BR)

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BR: Bendamustine, Rituximab

Regimen variant #1, 4 cycles

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

Chemotherapy

Bendamustine 90 mg/m² IV once per day on days 2 & 3

Targeted therapy

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

28-day cycle for 4 cycles

Regimen variant #2, indefinite

Study	Evidence
Treon et al. 2011	Phase II

Chemotherapy

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

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once on either day 1 or 2

28-day cycles

References

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
Treon SP, Hanzis C, Tripsas C, Ioakimidis L, Patterson CJ, Manning RJ, Sheehy P. Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):133-5. link to original article contains protocol PubMed

Cladribine & Rituximab

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Regimen

Study	Evidence
Laszlo et al. 2010	Phase II

Chemotherapy

Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 5

Targeted therapy

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

1-month cycle for 4 cycles

References

Laszlo D, Andreola G, Rigacci L, Fabbri A, Rabascio C, Mancuso P, Pruneri G, Radice D, Pinto A, Frigeri F, Calabrese L, Billio A, Bertolini F, Martinelli G. Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study. J Clin Oncol. 2010 May 1;28(13):2233-8. Epub 2010 Apr 5. link to original article contains verified protocol PubMed IEURONC_*II_204_003

Everolimus monotherapy

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Regimen

Study	Evidence
Ghobrial et al. 2010 (MC048G)	Phase II

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day while fasting

Supportive medications

WBC growth factors per physician discretion if neutropenia occurred, but it was not to be used prophylactically in order to maintain dosing.
Erythropoietin for anemia allowed per physician discretion.

28-day cycles

References

MC048G: Ghobrial IM, Gertz M, Laplant B, Camoriano J, Hayman S, Lacy M, Chuma S, Harris B, Leduc R, Rourke M, Ansell SM, Deangelo D, Dispenzieri A, Bergsagel L, Reeder C, Anderson KC, Richardson PG, Treon SP, Witzig TE. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1408-14. Epub 2010 Feb 8. link to original article contains verified protocol link to PMC article PubMed NCT00436618
1. Update: Ghobrial IM, Witzig TE, Gertz M, LaPlant B, Hayman S, Camoriano J, Lacy M, Bergsagel PL, Chuma S, DeAngelo D, Treon SP. Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom Macroglobulinemia. Am J Hematol. 2014 Mar;89(3):237-42. link to original article PubMed

Fludarabine & Rituximab (FR)

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FR: Fludarabine & Rituximab

Regimen

Study	Years of enrollment	Evidence
Treon et al. 2008 (UCLA-0101063)	2001-2003	Phase II, <20 pts in subgroup

Chemotherapy

Fludarabine (Fludara) as follows:
- Cycles 2 to 4: 25 mg/m² (route not specified) once per day on days 1 to 5
- Cycles 5 to 7: 25 mg/m² (route not specified) once per day on days 8 to 12

Targeted therapy

Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
- Cycle 5: 375 mg/m² IV once per day on days 1 & 8
- Cycle 8: 375 mg/m² IV once per day on days 15 & 22

28-day cycle for 8 cycles

References

UCLA-0101063: Treon SP, Branagan AR, Ioakimidis L, Soumerai JD, Patterson CJ, Turnbull B, Wasi P, Emmanouilides C, Frankel SR, Lister A, Morel P, Matous J, Gregory SA, Kimby E. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood. 2009 Apr 16;113(16):3673-8. Epub 2008 Nov 17. link to original article contains verified protocol link to PMC article PubMed NCT00020800

Ibrutinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Treon et al. 2015 (DFCI 12-015)	2012-2013	Phase II (RT)
Dimopoulos et al. 2016 (iNNOVATE substudy)	2014-2015	Non-randomized

Targeted therapy

Ibrutinib (Imbruvica) 420 mg PO once per day

28-day cycle for up to 26 cycles (2 years)

References

DFCI 12-015: Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015 Apr 9;372(15):1430-40. link to original article PubMed NCT01614821
1. Subgroup analysis: Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenström's macroglobulinemia. N Engl J Med. 2015 Aug 6;373(6):584-6. link to original article PubMed
2. Update: Treon SP, Meid K, Gustine J, Yang G, Xu L, Liu X, Patterson CJ, Hunter ZR, Branagan AR, Laubach JP, Ghobrial IM, Palomba ML, Advani R, Castillo JJ. Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. J Clin Oncol. 2021 Feb 20;39(6):565-575. Epub 2020 Sep 15. link to original article PubMed
iNNOVATE substudy: Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, García-Sanz R, Cornell RF, de Larrea CF, Castillo JJ, Granell M, Kyrtsonis MC, Leblond V, Symeonidis A, Kastritis E, Singh P, Li J, Graef T, Bilotti E, Treon S, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017 Feb;18(2):241-250. Epub 2016 Dec 9. link to original article contains protocol PubMed NCT02165397

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, <20 pts in this subgroup

Targeted therapy

Idelalisib (Zydelig) 150 mg PO twice per day

Continued indefinitely

References

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 Jan 22. link to original article contains verified protocol link to PMC article PubMed NCT01282424
1. Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708 link to abstract

Lenalidomide monotherapy

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Regimen

Study	Evidence
Fouquet et al. 2015 (RV-WM-0426)	Phase I/II, <20 pts

This is the MTD determined in the phase I portion of the study.

Targeted therapy

Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21

28-day cycles

References

RV-WM-0426: Fouquet G, Guidez S, Petillon MO, Louni C, Ohyba B, Dib M, Poulain S, Herbaux C, Martin A, Thielemans B, Brice P, Choquet S, Bakala J, Bories C, Demarquette H, Nudel M, Tournilhac O, Arnulf B, LeGouill S, Morel P, Banos A, Karlin L, Salles G, Leblond V, Leleu X. Lenalidomide is safe and active in Waldenström macroglobulinemia. Am J Hematol. 2015 Nov;90(11):1055-9. Epub 2015 Oct 6. link to original article contains protocol PubMed NCT02302469

Panobinostat monotherapy

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Regimen

Study	Evidence
Ghobrial et al. 2013 (DFCI 09-071)	Phase II

Targeted therapy

Panobinostat (Farydak) 30 mg PO 3 days per week (Mondays, Wednesdays, and Fridays)

28-day cycles

References

DFCI 09-071: Ghobrial IM, Campigotto F, Murphy TJ, Boswell EN, Banwait R, Azab F, Chuma S, Kunsman J, Donovan A, Masood F, Warren D, Rodig S, Anderson KC, Richardson PG, Weller E, Matous J. Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenstrom macroglobulinemia. Blood. 2013 Feb 21;121(8):1296-303. Epub 2013 Jan 3. link to original article contains verified protocol link to PMC article PubMed NCT00936611

RVR

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RVR: RAD-001 (Everolimus), Velcade (Bortezomib), Rituximab

Regimen

Study	Evidence
Ghobrial et al. 2015 (DFCI 09-280)	Phase I/II

These are the doses of the phase II portion of the study.

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day
Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1, 8, 15
Rituximab (Rituxan) as follows:
- Cycles 1 & 4: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 6 cycles

Subsequent treatment

Everolimus maintenance

References

DFCI 09-280: Ghobrial IM, Redd R, Armand P, Banwait R, Boswell E, Chuma S, Huynh D, Sacco A, Roccaro AM, Perilla-Glen A, Noonan K, MacNabb M, Leblebjian H, Warren D, Henrick P, Castillo JJ, Richardson PG, Matous J, Weller E, Treon SP. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia. 2015 Dec;29(12):2338-46. Epub 2015 Jul 3. link to original article contains verified protocol PubMed NCT01125293

VR

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VR: Velcade (Bortezomib) & Rituximab

Regimen

Study	Evidence
Ghobrial et al. 2010 (DFCI 06-008)	Phase II

Targeted therapy

Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1, 8, 15
Rituximab (Rituxan) as follows:
- Cycles 1 to 4: 375 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

"At the time of initiation of the study, the incidence of herpes zoster reactivation with bortezomib in WM was not well documented; therefore, antiviral prophylaxis was not mandated."

28-day cycle for up to 6 cycles

References

DFCI 06-008: Ghobrial IM, Hong F, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1422-8. Epub 2010 Feb 8. link to original article contains verified protocol link to PMC article PubMed NCT00422799
1. Update: Ghobrial IM, Xie W, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Poon T, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia. Am J Hematol. 2010 Sep;85(9):670-4. link to original article contains verified protocol PubMed

Maintenance after subsequent lines of therapy

Everolimus monotherapy

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Regimen

Study	Evidence
Ghobrial et al. 2015 (DFCI 09-280)	Phase II

Preceding treatment

RVR x 6

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day

Continued indefinitely

References

DFCI 09-280: Ghobrial IM, Redd R, Armand P, Banwait R, Boswell E, Chuma S, Huynh D, Sacco A, Roccaro AM, Perilla-Glen A, Noonan K, MacNabb M, Leblebjian H, Warren D, Henrick P, Castillo JJ, Richardson PG, Matous J, Weller E, Treon SP. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia. 2015 Dec;29(12):2338-46. Epub 2015 Jul 3. link to original article contains verified protocol PubMed NCT01125293

Response criteria

Current

2012: Response assessment in Waldenström macroglobulinaemia: Update from the VIth International Workshop

Older

2003: Uniform response criteria in Waldenstrom's macroglobulinemia: Consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia

@@ Line 657: / Line 657: @@
 ## '''Update:''' Dhodapkar MV, Hoering A, Gertz MA, Rivkin S, Szymonifka J, Crowley J, Barlogie B. Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood. 2009 Jan 22;113(4):793-6. Epub 2008 Oct 17. [http://www.bloodjournal.org/content/113/4/793.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630265/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18931340 PubMed]
-==FR {{#subobject:49db19|Regimen=1}}==
+==Fludarabine & Rituximab (FR) {{#subobject:49db19|Regimen=1}}==
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@@ Line 878: / Line 878: @@
 |2003-2010
 |style="background-color:#1a9851"|Phase III (E-switch-ic)
-|[[#FR_2|FR]]
+|[[#Fludarabine_.26_Rituximab.28FR.29_2|FR]]
 |style="background-color:#91cf60"|Seems to have superior OS
 |-
@@ Line 894: / Line 894: @@
 # '''StiL NHL 2-2003:''' Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study Group indolent Lymphomas. 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00447-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26655425 PubMed] NCT01456351
-==FR {{#subobject:f36d77|Regimen=1}}==
+==Fludarabine & Rituximab (FR) {{#subobject:f36d77|Regimen=1}}==
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@@ Line 1,211: / Line 1,211: @@
 ## '''Update:''' Ghobrial IM, Witzig TE, Gertz M, LaPlant B, Hayman S, Camoriano J, Lacy M, Bergsagel PL, Chuma S, DeAngelo D, Treon SP. Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom Macroglobulinemia. Am J Hematol. 2014 Mar;89(3):237-42. [https://onlinelibrary.wiley.com/doi/10.1002/ajh.23620/full link to original article] [https://pubmed.ncbi.nlm.nih.gov/24716234 PubMed]
-==FR {{#subobject:9598c5|Regimen=1}}==
+==Fludarabine & Rituximab (FR) {{#subobject:9598c5|Regimen=1}}==
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Difference between revisions of "Waldenström macroglobulinemia"

Revision as of 01:49, 9 December 2021

Guidelines

EMN

ESMO

Older

"How I Treat"

IWWM

Current

Older

NCCN

First-line therapy, randomized data

Bendamustine & Rituximab (BR)

Regimen

Chemotherapy

Targeted therapy

Supportive medications

Subsequent treatment

References

Chlorambucil monotherapy

Regimen

Chemotherapy

Supportive medications

References

Fludarabine monotherapy

Regimen

Chemotherapy

Supportive medications

References

Ibrutinib monotherapy

Regimen

Targeted therapy

References

Ibrutinib & Rituximab

Regimen

Targeted therapy

References

Rituximab monotherapy

Regimen variant #1, single course (4 doses)

Targeted therapy

Regimen variant #2, "extended" course (8 doses)

Targeted therapy

References

R-CHOP

Regimen variant #1

Targeted therapy

Chemotherapy

Regimen variant #2

Targeted therapy

Chemotherapy

References

Zanubrutinib monotherapy

Regimen variant #1

Targeted therapy

Regimen variant #2

Targeted therapy

References

First-line therapy, non-randomized or retrospective data

BDR

Regimen variant #1

Targeted therapy

Chemotherapy

Supportive medications

Regimen variant #2

Targeted therapy

Chemotherapy

Supportive medications

References

CaRD

Regimen

Targeted therapy

Chemotherapy

Supportive medications

References

Cladribine & Rituximab

Regimen

Chemotherapy

Targeted therapy

References

DRC