Waldenström macroglobulinemia

Section editor
	Samuel M. Rubinstein, MD University of North Carolina Chapel Hill, NC, USA LinkedIn

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39 regimens on this page 48 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

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. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2013: Buske et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

IWWM

• 2020: Castillo et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia PubMed
• 2016: Leblond et al. Treatment recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia PubMed
• 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

• 2012: Anderson et al. Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013. PubMed

First-line therapy, randomized data

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008	Phase 3, fewer than 20 pts in this subgroup (E-switch-ic)	R-CHOP	Superior PFS (primary endpoint)
Awaiting publication (MAINTAIN)	2009-2012	Non-randomized part of phase 3 RCT

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 therapy

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

28-day cycle for up to 6 cycles; StiL NHL1 gave 2 additional cycles of rituximab only

Subsequent treatment

• MAINTAIN: Observation versus rituximab maintenance

References

1. MAINTAIN: 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-). ASH Annual Meeting Abstracts 2012 120: 2739. NCT00877214
2. 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 dosing details in manuscript have been reviewed by our editors 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

Chlorambucil monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leblond et al. 2012 (WM1)	2001-2009	Phase 3 (E-switch-ic)	Fludarabine	Inferior OS (secondary endpoint)

Eligibility criteria

• At least 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) by the following age-based criteria:
  • 75 years old or younger: 8 mg/m² PO once per day on days 1 to 10
  • Older than 75 years old: 6 mg/m² PO once per day on days 1 to 10

Supportive therapy

• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00566332; NCT00608374

DRC

DRC: Dexamethasone, Rituximab, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2007 (ECWM-1 phase 2)	2002-2006	Phase 2
Awaiting publication (RAINBOWWM)	2020-2029	Phase 3 (C)	RI	TBD if different co-primary endpoints of ORR6/PFS

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." To our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV once on day 1, given first

Chemotherapy

• 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

1. ECWM-1 phase 2: 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. Epub 2007 Jun 18. link to original article dosing details in manuscript have been reviewed by our editors 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
2. RAINBOW_WM: NCT04061512

DRC (SC rituximab)

DRC: Dexamethasone, Rituximab, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Buske et al. 2023 (ECWM-1)	Not reported	Phase 3 (C)	B-DRC	Did not meet primary endpoint of PFS

Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once on day 1

Chemotherapy

• 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) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
• Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
  • Cycles 2 to 6: 1400 SC once on day 1

28-day cycle for 6 cycles

References

1. ECWM-1: Buske C, Dimopoulos MA, Grunenberg A, Kastritis E, Tomowiak C, Mahé B, Troussard X, Hajek R, Viardot A, Tournilhac O, Aurran T, Lepretre S, Zerazhi H, Hivert B, Leblond V, de Guibert S, Brandefors L, Garcia-Sanz R, Gomes da Silva M, Kimby E, Schmelzle B, Kaszynski D, Dreyhaupt J, Muche R, Morel P. Bortezomib-Dexamethasone, Rituximab, and Cyclophosphamide as First-Line Treatment for Waldenström's Macroglobulinemia: A Prospectively Randomized Trial of the European Consortium for Waldenström's Macroglobulinemia. J Clin Oncol. 2023 May 10;41(14):2607-2616. Epub 2023 Feb 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01788020

Fludarabine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leblond et al. 2012 (WM1)	2001-2009	Phase 3 (E-switch-ic)	Chlorambucil	Superior OS (secondary endpoint)

Eligibility criteria

• At least 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) by the following age-based criteria:
  • 75 years old or younger: 40 mg/m² PO once per day on days 1 to 5
  • Older than 75 years old: 30 mg/m² PO once per day on days 1 to 5

Supportive therapy

• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00566332; NCT00608374

Ibrutinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Treon et al. 2018 (DFCI 15-359)	2016	Phase 2
Tam et al. 2020 (ASPEN)	2017-01 to 2018-07	Phase 3 (C)	Zanubrutinib	Seems to have inferior composite CR/VGPR rate1
Awaiting publication (CZAR-1)	2021-2028	Phase 3 (C)	Carfilzomib & Ibrutinib	TBD if different composite primary endpoint of CR/VGPR rate

¹Reported efficacy is based on the 2022 abstract update.

Biomarker eligibility criteria

• ASPEN: MYD88 p.L265P

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT02604511
2. 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. Epub 2020 Jul 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03053440
   1. Update: Dimopoulos MA, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. J Clin Oncol. 2023 Nov 20;41(33):5099-5106. Epub 2023 Jul 21. link to original article link to PMC article PubMed

1. CZAR-1: NCT04263480

Ibrutinib & Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase 3 (E-RT-esc)	Rituximab	Superior PFS1 (primary endpoint) Median PFS: NYR vs 20.3 mo (HR 0.25, 95% CI 0.15-0.42)

¹Reported efficacy is based on the 2021 update.

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
• Rituximab (Rituxan) as follows:
  • Cycles 1 & 5: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02165397
   1. Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article PubMed

Rituximab monotherapy

Regimen variant #1, single course (4 doses)

Study	Dates of enrollment	Evidence
Gertz et al. 2004 (ECOG E3A98)	2000-04-06 to 2002-01-25	Phase 2

Targeted therapy

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

7-day cycle for 4 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2002	1999-2001	Phase 2
Dimopoulos et al. 2002a	1999-2002	Phase 2, fewer than 20 pts in subgroup
Treon et al. 2005	Not reported	Phase 2, fewer than 20 pts in subgroup
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase 3 (C)	Ibrutinib & Rituximab	Inferior PFS

Note: In Treon et al. 2005, the second course began at the equivalent of cycle 4.

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, 15, 22

28-day cycle for 5 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed
4. 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 dosing details in manuscript have been reviewed by our editors PubMed
5. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02165397
   1. Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article PubMed

R-CHOP

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

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008	Phase 3, fewer than 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

Glucocorticoid therapy

• 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Buske et al. 2009	2000-2003	Phase 3 (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

Glucocorticoid therapy

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

21-day cycle for 4 to 8 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors 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

Zanubrutinib monotherapy

Regimen variant #1

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tam et al. 2020 (ASPEN)	2017-01 to 2018-07	Phase 3 (E-RT-switch-ic)	Ibrutinib	Seems to have superior composite CR/VGPR rate1 (primary endpoint) CR/VGPR rate: 36% vs 22%

¹Reported efficacy is based on the 2022 abstract update.

Biomarker eligibility criteria

• ASPEN: MYD88 p.L265P

Targeted therapy

• Zanubrutinib (Brukinsa) 160 mg PO twice per day on days 1 to 28

28-day cycles

Regimen variant #2

FDA-recommended dose

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

Targeted therapy

• Zanubrutinib (Brukinsa) 320 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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. Epub 2020 Jul 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03053440
   1. Update: Dimopoulos MA, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernández de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trněný M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. J Clin Oncol. 2023 Nov 20;41(33):5099-5106. Epub 2023 Jul 21. link to original article link to PMC article PubMed

First-line therapy, non-randomized or retrospective data

BDR

BDR: Bortezomib, Dexamethasone, Rituximab

Regimen variant #1

Study	Dates of enrollment	Evidence
Treon et al. 2009 (WMCTG 05-180)	2005 to not reported	Phase 2

Note: some details are missing in Treon et al. 2009; the updated abstract provides these additional details. As shown here, there is no treatment in "cycle 5", which is an intentional 12-week pause.

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 4: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
  • Cycles 6 to 9: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
• Rituximab (Rituxan) as follows:
  • Cycles 1 to 4: 375 mg/m² IV once on day 11
  • Cycles 6 to 9: 375 mg/m² IV once on day 11

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg IV once per day on days 1, 4, 8, 11
  • Cycles 6 to 9: 40 mg IV once per day on days 1, 4, 8, 11

Supportive therapy

• 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, given the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity."

21-day cycle for 4 cycles, then 12-week cycle for 5 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Dimopoulos et al. 2013 (BDR-WM)	2007-03 to 2010-06	Phase 2

Note: 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: 375 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

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

Supportive therapy

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

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

References

1. 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 dosing details in manuscript have been reviewed by our editors 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
2. 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 dosing details in manuscript have been reviewed by our editors 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. Epub 2016 Nov 21. link to original article PubMed

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Ghobrial et al. 2010 (DFCI 06-008)	2006-2008	Phase 2

Targeted therapy

• 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

Supportive therapy

• "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

1. 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 dosing details in manuscript have been reviewed by our editors 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. Epub 2010 Aug 25. link to original article dosing details in manuscript have been reviewed by our editors PubMed

CaRD

CaRD: Carfilzomib, Rituximab, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Treon et al. 2014 (DFCI 11-279)	2011 to not reported	Phase 2

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 20 minutes once per day on days 1, 2, 8, 9
  • Cycles 2 to 6: 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

Glucocorticoid therapy

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

Supportive therapy

• 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 prior to rituximab 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

Subsequent treatment

• DFCI 11-279, patients with SD or better: CaRD maintenance, beginning 8 weeks later

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01470196

Cladribine & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Laszlo et al. 2010	2003-12 to 2007-02	Phase 2

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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed IEURONC_*II_204_003

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence
Treon et al. 2016 (WMCTG 09-214)	2009-2011	Phase 2

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT00976248

FCR

FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen

Study	Dates of enrollment	Evidence
Tedeschi et al. 2011	2005-2008	Phase 2

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 therapy

• Diphenhydramine (Benadryl) (dose not specified) IV once on day 1, prior to rituximab
• Acetaminophen (Tylenol) (dose not specified) PO once on day 1, prior to rituximab
• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

Fludarabine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Dhodapkar et al. 2001 (SWOG S9003)	1992-1998	Phase 2

Chemotherapy

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

28-day cycle for 4 to 8 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors 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)

FR: Fludarabine & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Treon et al. 2008 (UCLA-0101063)	2001-2003	Phase 2

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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00020800

IDR

IDR: Ixazomib, Dexamethasone, Rituximab

Regimen

Study	Dates of enrollment	Evidence
Castillo et al. 2018 (DFCI 14-559)	2015-2016	Phase 2

Targeted therapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
• Rituximab (Rituxan) as follows:
  • Cycles 3 to 12: 375 mg/m² IV once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15

28-day cycle for 6 cycles, then 56-day cycle for 6 cycles

References

1. DFCI 14-559: Castillo JJ, Meid K, Gustine JN, Dubeau T, Severns P, Hunter ZR, Yang G, Xu L, Treon SP. Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenström Macroglobulinemia. Clin Cancer Res. 2018 Jul 15;24(14):3247-3252. Epub 2018 Apr 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02400437
   1. Update: Castillo JJ, Meid K, Flynn CA, Chen J, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Patterson CJ, Yang G, Hunter Z, Treon SP. Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up. Blood Adv. 2020 Aug 25;4(16):3952-3959. link to original article link to PMC article PubMed

PCR

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

Regimen

Study	Dates of enrollment	Evidence
Herth et al. 2014	2005-2010	Phase 2

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) as follows:
  • Cycle 1, WBC up to 50 x 10⁹/L: 375 mg/m² IV once on day 1
  • Cycles 2 to 6: 375 mg/m² IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Herth et al. 2014, patients with PR/CR: Rituximab maintenance

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

Thalidomide & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Treon et al. 2008 (DFCI 03-077)	2003 to not reported	Phase 2

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 on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00142116

Thioguanine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Weiss et al. 1963	1962	Pilot

Note: This regimen is of historic interest.

Chemotherapy

• Thioguanine (Tabloid)

References

1. 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

Maintenance after first-line therapy

CaRD

CaRD: Carfilzomib, Rituximab, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Treon et al. 2014 (DFCI 11-279)	2011 to not reported	Phase 2

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

Glucocorticoid therapy

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

8-week cycle for 8 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01470196

Rituximab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Herth et al. 2014	2005-2010	Phase 2

Preceding treatment

• PER induction x 6

Targeted therapy

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

3-month cycle for 8 cycles (2 years)

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

Relapsed or refractory, randomized data

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase 3 (E-switch-ic)	FR	Seems to have superior OS (secondary endpoint)

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

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT01456351

Fludarabine & Rituximab (FR)

FR: Fludarabine & Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase 3 (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

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT01456351

Ibrutinib & Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase 3 (E-RT-esc)	Rituximab	Superior PFS1 (primary endpoint) Median PFS: NYR vs 20.3 mo (HR 0.25, 95% CI 0.15-0.42)

¹Reported efficacy is based on the 2021 update.

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
• Rituximab (Rituxan) as follows:
  • Cycles 1 & 5: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02165397
   1. Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article PubMed

Rituximab monotherapy

Regimen variant #1, single course (4 doses)

Study	Dates of enrollment	Evidence
Gertz et al. 2004 (ECOG E3A98)	2000-04-06 to 2002-01-25	Phase 2

Targeted therapy

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

7-day cycle for 4 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2002	1999-2001	Phase 2
Treon et al. 2005	Not reported	Phase 2, fewer than 20 pts in subgroup
Dimopoulos et al. 2018 (iNNOVATE)	2014-2016	Phase 3 (C)	Ibrutinib & Rituximab	Inferior PFS

Note: In Treon et al. 2005, the second course began at the equivalent of cycle 4.

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, 15, 22

28-day cycle for 5 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02165397
   1. Update: Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. Epub 2021 Oct 4. link to original article link to PMC article PubMed

Relapsed or refractory, non-randomized or retrospective data

Alemtuzumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Hale et al. 1988	1987-1988	Pilot
Treon et al. 2011 (DFCI 02-079)	Not reported	Phase 2

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 therapy

• 1 L of normal saline, prior to alemtuzumab
• Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 3, 5, prior to alemtuzumab
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 3, 5, prior to alemtuzumab
• Hydrocortisone (Cortef) 100 to 200 mg IV once per day on days 1, 3, 5, prior to alemtuzumab if patient had a prior reaction
• Cimetidine (Tagamet) 300 mg IV once per day on days 1, 3, 5, prior to alemtuzumab 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

1. 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
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00142181

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen variant #1, 4 cycles

Study	Dates of enrollment	Evidence
Rummel et al. 2005	2000-07 to 2003-07	Phase 2, fewer than 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	Dates of enrollment	Evidence
Treon et al. 2011	Not reported	Retrospective

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

1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. Retrospective: 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 dosing details in abstract have been reviewed by our editors PubMed

Bortezomib monotherapy

Regimen variant #1, 4 cycles

Study	Dates of enrollment	Evidence
Dimopoulos et al. 2005	Not reported	Phase 2, fewer than 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	Dates of enrollment	Evidence
Treon et al. 2007 (WMCTG 03-248)	Not reported	Phase 2

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	Dates of enrollment	Evidence
Chen et al. 2007 (NCIC-CTG I152)	2003-01 to 2005-03	Phase 2

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

1. 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 dosing details in abstract have been reviewed by our editors PubMed
2. 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. Epub 2007 Mar 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00045695
3. 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 dosing details in manuscript have been reviewed by our editors PubMed

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Ghobrial et al. 2010 (DFCI 06-008)	2006-2008	Phase 2

Targeted therapy

• 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

Supportive therapy

• "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

1. 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 dosing details in manuscript have been reviewed by our editors 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. Epub 2010 Aug 25. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Cladribine & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Laszlo et al. 2010	2003-12 to 2007-02	Phase 2

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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed IEURONC_*II_204_003

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence
Ghobrial et al. 2010 (MC048G)	2006-04 to 2008-08	Phase 2

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28, taken on an empty stomach

Supportive therapy

• 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

1. 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 dosing details in manuscript have been reviewed by our editors 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)

FR: Fludarabine & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Treon et al. 2008 (UCLA-0101063)	2001-2003	Phase 2, fewer than 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00020800

Ibrutinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Treon et al. 2015 (DFCI 12-015)	2012-2013	Phase 2 (RT)
Dimopoulos et al. 2016 (iNNOVATE substudy)	2014-2015	Non-randomized

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28

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

References

1. 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 link to PMC article PubMed
2. 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 dosing details in abstract have been reviewed by our editors PubMed NCT02165397

Idelalisib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Gopal et al. 2014 (DELTA)	2011-2012	Phase 2, fewer than 20 pts in this subgroup

Targeted therapy

• Idelalisib (Zydelig) 150 mg PO twice per day

Continued indefinitely

References

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

Lenalidomide monotherapy

Regimen

Study	Dates of enrollment	Evidence
Fouquet et al. 2015 (RV-WM-0426)	2009 to not reported	Phase 1/2, fewer than 20 pts

Note: This is the MTD determined in the phase 1 portion of the study.

Targeted therapy

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

28-day cycles

References

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT02302469

RVR

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

Regimen

Study	Dates of enrollment	Evidence
Ghobrial et al. 2015 (DFCI 09-280)	2010-2013	Phase 1/2

Note: These are the doses of the phase 2 portion of the study.

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28
• Bortezomib (Velcade) as follows:
  • Cycles 1 to 6: 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 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01125293

Venetoclax monotherapy

Regimen

Study	Dates of enrollment	Evidence
Castillo et al. 2021 (DFCI 15-491)	2016-06 to 2018-02	Phase 2

Note: this dosing is a mid-protocol modification.

Targeted therapy

• Venetoclax (Venclexta) as follows:
  • Cycle 1: 400 mg PO once per day on days 1 to 7, then 800 mg PO once per day on days 8 to 28
  • Cycles 2 to 26: 800 mg PO once per day on days 1 to 28

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

References

1. DFCI 15-491: Castillo JJ, Allan JN, Siddiqi T, Advani RH, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Furman RR, Treon SP. Venetoclax in Previously Treated Waldenström Macroglobulinemia. J Clin Oncol. 2022 Jan 1;40(1):63-71. Epub 2021 Nov 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02677324

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