Waldenström macroglobulinemia

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35 regimens on this page
41 variants on this page

Contents


Guidelines

IWWM

Current

Older

Untreated, randomized data

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Rummel et al. 2012 (StiL NHL 7-2008 (MAINTAIN) Non-randomized
Rummel et al. 2013 (StiL NHL1) Phase III, <20 pts in this subgroup R-CHOP Superior PFS

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

Chemotherapy

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

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; Rummel et al. 2012 gave 2 additional cycles of rituximab only

Patients in MAINTAIN were randomized to observation versus rituximab maintenance. Results have not yet been announced.

References

  1. 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
  2. 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; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article contains verified protocol PubMed
    1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. ASH Annual Meeting 2014, Abstract 4407 link to abstract

Chlorambucil (Leukeran)

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Regimen

Study Evidence Comparator Efficacy
Leblond et al. 2012 (WM1) Phase III Fludarabine Inferior OS

This regimen was intended for patients ≥ 18 years old with previously untreated WM and an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2.

Chemotherapy

  • Chlorambucil (Leukeran) as follows:
    • Age ≤ 75 years: 8 mg/m2 PO once per day on days 1 to 10
    • Age > 75 years: 6 mg/m2 PO once per day on days 1 to 10

Supportive medications

28-day cycle for up to 12 cycles

References

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

Fludarabine (Fludara)

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Regimen

Study Evidence Comparator Efficacy
Leblond et al. 2012 (WM1) Phase III Chlorambucil Superior OS

This regimen was intended for patients ≥ 18 years old with previously untreated WM and an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2.

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Age ≤ 75 years: 40 mg/m2 PO once per day on days 1 to 5
    • Age > 75 years: 30 mg/m2 PO once per day on days 1 to 5

Supportive medications

28-day cycle for up to 6 cycles

References

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

R-CHOP

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

Synonyms: R-CHOP-21, CHOP-R

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

Regimen

Study Evidence Comparator Efficacy
Rummel et al. 2013 (StiL NHL1) Phase III, <20 pts in this subgroup BR Inferior PFS

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

Chemotherapy

21-day cycle for up to maximum of 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Buske et al. 2009 Phase III CHOP Superior TTF

Chemotherapy

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 contains verified protocol PubMed
  2. 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; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article contains verified protocol PubMed
    1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. ASH Annual Meeting 2014, Abstract 4407 link to abstract

Untreated, non-randomized or retrospective data

BDR

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BDR: Bortezomib, Dexamethasone, Rituximab

Regimen #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.

Chemotherapy

Supportive medications

  • Varicella zoster (shingles) prophylaxis with ONE of the following recommended:
  • "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 ≥ 5,000 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 #2

Study Evidence
Dimopoulos et al. 2013 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.

Chemotherapy

  • 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 week on days 1, 8, 15, 22
  • Dexamethasone (Decadron) as follows:
    • Cycles 2 and 5 only: 40 mg IV once per week on days 1, 8, 15, 22
  • Rituximab (Rituxan) as follows:
    • Cycles 2 and 5 only: 375 mg/m2 IV once per week on days 1, 8, 15, 22

Supportive medications

35-day cycle for 5 cycles (Cycle 1 is a 21-day cycle)

References

  1. 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. 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 PMC article contains verified protocol PubMed content property of HemOnc.org
    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. contains protocol link to abstract
  2. 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
    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

Bortezomib & Rituximab

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Regimen

Study Evidence
Ghobrial et al. 2010 Phase II

Chemotherapy

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

  1. 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

CaRD

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CaRD: Carfilzomib, Rituximab, Dexamethasone

Regimen

Study Evidence
Treon et al. 2014 Phase II

Chemotherapy

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

Supportive medications

21-day cycle for 6 cycles

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

References

  1. 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

Cladribine & Rituximab

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Regimen

Study Evidence
Laszlo et al. 2010 Phase II

Chemotherapy

Monthly 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 contains verified protocol PubMed

DRC

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DRC: Dexamethasone, Rituximab, Cyclophosphamide

Regimen

Study Evidence
Dimopoulos et al. 2007 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

21-day cycle for 6 cycles

References

  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
    1. Update: Abstract: Dimopoulos, Meletios A., Roussou, Maria, Kastritis, Efstathios, Hadjiharissi, Evdoxia, Kyrtsonis, Marie-Christine, Symeonidis, Argiris, Repoussis, Panagiotis, Michalis, Eurydiki, Delimpasi, Sosana, Tsatalas, Konstantinos, Tsirigotis, Panagiotis, Vassou, Amalia, Vervessou, Elina, Katodritou, Eirini, Gavriatopoulou, Maria, Gika, Dimitra, Terpos, Evangelos, Zervas, Konstantinos. Primary Treatment of Waldenstrom's Macroglobulinemia with Dexamethasone, Rituximab and Cyclophosphamide (DRC): Final Analysis of a Phase II Study. ASH Annual Meeting Abstracts 2012 120: 438 link to abstract
    2. 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 (Afinitor)

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Regimen

Study Evidence
Treon et al. 2011 Phase II

Chemotherapy

28-day cycles, given until progression or unacceptable toxicity

References

  1. Abstract: Treon, Steven P, Tripsas, Christina K, Ioakimidis, Leukothea, Warren, Diane, Patterson, Christopher, Heffner, Leonard, Eradat, Herbert, Gregory, Stephanie A., Thomas, Sheeba, Advani, Ranjana, Baz, Rachid, Badros, Ashraf Z., Matous, Jeffrey, Anderson, Kenneth C., Ghobrial, Irene M. Prospective, Multicenter Study of the MTOR Inhibitor Everolimus (RAD001) As Primary Therapy in Waldenstrom's Macroglobulinemia. ASH Annual Meeting Abstracts 2011 118: 2951 link to abstract
    1. Update: Abstract: Steven Peter Treon, MD, MA, PhD, Christina K Tripsas, Kirsten Meid, Christopher Patterson, Leonard T Heffner, Herbert Eradat, Stephanie A. Gregory, Sheeba K. Thomas, Ranjana H. Advani, Rachid Baz, Ashraf Z. Badros, Jeffrey Matous, Timothy J. Murphy, Irene M. Ghobrial. Prospective, Multicenter Study Of The Mtor Inhibitor Everolimus (RAD001) As Primary Therapy In Waldenstrom’s Macroglobulinemia. Blood Nov 2013,122(21)1822 link to abstract

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen

Study Evidence
Tedeschi et al. 2011 Phase II

Chemotherapy

Supportive medications

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 contains verified protocol PubMed

Fludarabine (Fludara)

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Regimen

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

Chemotherapy

28-day cycle for 4 to 8 cycles

References

  1. 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. 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 PubMed

Fludarabine & Rituximab

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Regimen

Study Evidence
Treon et al. 2008 Phase II

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Weeks 5, 9, 13, 19, 23, 27: 25 mg/m2 (route not specified) once per day on days 1 to 5
  • Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 1 to 4, 17, 18, 30, 31 (8 doses total)

One course

References

  1. 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 PubMed

Ofatumumab (Arzerra)

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Regimen

Study Evidence
Furman et al. 2016 Phase II

Note: This study used two dosing schemas, based on a mid-study amendment. See paper for details about redosing based on response. It is not clear from the abstract how many patients were untreated versus relapsed.

Chemotherapy

  • Ofatumumab (Arzerra) as follows (choose one):
    • Option 1: 300 mg IV once on week 1 and 1000 mg IV once per week on weeks 2 to 4
    • Option 2: 300 mg IV once on week 1 and 2000 mg IV once per week on weeks 2 to 5

4-week or 5-week course

References

  1. Furman RR, Eradat HA, DiRienzo CG, Hofmeister CC, Hayman SR, Leonard JP, Coleman M, Advani R, Chanan-Khan A, Switzky J, Liao QM, Shah D, Jewell RC, Lisby S, Lin TS. Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study. Lancet Haematol. 2017 Jan;4(1):e24-e34. Epub 2016 Nov 30. link to original article contains protocol PubMed

PER

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PER: Pentostatin, Endoxan (Cyclophosphamide), Rituximab

Regimen

Study Evidence
Herth et al. 2014 Phase II

Chemotherapy

21-day cycle for 6 cycles

Patients with CR/PR proceeded to 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 contains verified protocol PubMed

Rituximab (Rituxan)

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Regimen #1, "extended" course

Study Evidence
Treon et al. 2005 (WMCTG) Phase II, <20 pts in subgroup

Note: the abstract says that rituximab was given weeks 12 to 16 but this is likely a typo.

Chemotherapy

  • Rituximab (Rituxan) as follows:
    • Weeks 1 to 4: 375 mg/m2 IV once per week for four weeks
    • Weeks 12 to 15: 375 mg/m2 IV once per week for four weeks

One course (8 doses total)

Regimen #2, single course

Study Evidence
Gertz et al. 2004 (ECOG E3A98) Phase II

Chemotherapy

4-week course

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 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. PubMed
  3. 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
  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 contains verified protocol PubMed

Rituximab & Thalidomide

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Regimen

Study Evidence
Treon et al. 2008 Phase II

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 2 to 5 and weeks 13 to 16 (8 doses total)
  • Thalidomide (Thalomid) as follows:
    • 200 mg PO once per day x 2 weeks, then
    • 400 mg PO once per day x 50 weeks

52-week course

References

  1. 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 PubMed

Consolidation and/or maintenance after upfront therapy

CaRD

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CaRD: Carfilzomib, Rituximab, Dexamethasone

Regimen

Study Evidence
Treon et al. 2014 Phase II

Treatment preceded by CaRD induction x 6 cycles.

Chemotherapy

8-week cycle for 8 cycles

References

  1. 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

Rituximab (Rituxan)

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Regimen

Study Evidence
Herth et al. 2014 Phase II

Treatment preceded by PER x 6.

Chemotherapy

3-month cycle for 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 contains verified protocol PubMed

Relapsed/refractory, randomized data

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Rummel et al. 2015 (NHL 2-2003) Phase III Fludarabine & Rituximab Seems to have superior OS

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. link to original article contains protocol PubMed

Fludarabine & Rituximab

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Regimen

Study Evidence Comparator Efficacy
Rummel et al. 2015 (NHL 2-2003) Phase III BR Seems to have inferior OS

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. link to original article contains protocol PubMed

Relapsed/refractory, non-randomized or retrospective data

Alemtuzumab (Campath)

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Regimen

Study Evidence
Treon et al. 2011 Phase II

Per the authors, "Alemtuzumab is an active therapy.., but short- and long-term toxicities need to be carefully weighed against other available treatment options."

Chemotherapy

  • Alemtuzumab (Campath) as follows:
    • 3 test doses of 3 mg IV, 10 mg IV, and 30 mg IV over 1 week
    • 30 mg IV three times per week x 12 weeks (36 doses)

Supportive medications

13-week treatment course

References

  1. 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 PubMed

Allogeneic hematopoietic cell transplant

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Regimen

Study Evidence
Kyriakou et al. 2010 Retrospective

Retrospective series; included here for reference purposes only.

References

  1. Kyriakou C, Canals C, Cornelissen JJ, Socié G, Willemze R, Ifrah N, Greinix HT, Blaise D, Deconinck E, Ferrant A, Schattenberg A, Harousseau JL, Sureda A, Schmitz N. Allogeneic stem-cell transplantation in patients with Waldenström macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2010 Nov 20;28(33):4926-34. Epub 2010 Oct 18. link to original article PubMed

Bortezomib (Velcade)

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Regimen

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

Chemotherapy

Up to 8 cycles (cycle duration not defined)

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 PubMed
  2. 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 PubMed
  3. 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

Bortezomib & Rituximab

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Regimen

Study Evidence
Ghobrial et al. 2010 Phase II

Chemotherapy

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

  1. 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 PubMed

BR

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BR: Bendamustine, Rituximab

Regimen #1

Study Evidence
Treon et al. 2011 Phase II

Chemotherapy

28-day cycles

Regimen #2

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

Chemotherapy

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

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

28-day cycle for 4 cycles

References

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

Monthly 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 contains verified protocol PubMed

Everolimus (Afinitor)

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Regimen

Study Evidence
Ghobrial et al. 2010 Phase II

Chemotherapy

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, given until progression or unacceptable toxicity

References

  1. 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 PubMed
    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

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Regimen

Study Evidence
Treon et al. 2008 Phase II, <20 pts in subgroup

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Weeks 5, 9, 13, 19, 23, 27: 25 mg/m2 (route not specified) once per day on days 1 to 5
  • Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 1 to 4, 17, 18, 30, 31 (8 doses total)

One course

References

  1. 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 PubMed

Ibrutinib (Imbruvica)

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Regimen

Study Evidence
Treon et al. 2015 Phase II
Dimopoulos et al. 2016 (iNNOVATE) Non-randomized

Chemotherapy

Continuously for 2 years or until progression or unacceptable toxicity

References

  1. 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
    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. 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. Epub 2016 Dec 9.[Epub ahead of print] link to original article contains protocol PubMed

Idelalisib (Zydelig)

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

Regimen

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

Chemotherapy

Continued until progression, death, or unacceptable toxicity

References

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

Lenalidomide (Revlimid)

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Regimen

Study Evidence
Fouquet et al. 2015 Phase I/II, <20 pts

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

Chemotherapy

28-day cycles

References

  1. 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

Ofatumumab (Arzerra)

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Regimen

Study Evidence
Furman et al. 2016 Phase II

Note: This study used two dosing schemas, based on a mid-study amendment. See paper for details about redosing based on response. It is not clear from the abstract how many patients were untreated versus relapsed.

Chemotherapy

  • Ofatumumab (Arzerra) as follows (choose one):
    • Option 1: 300 mg IV once on week 1 and 1000 mg IV once per week on weeks 2 to 4
    • Option 2: 300 mg IV once on week 1 and 2000 mg IV once per week on weeks 2 to 5

4-week or 5-week course

References

  1. Furman RR, Eradat HA, DiRienzo CG, Hofmeister CC, Hayman SR, Leonard JP, Coleman M, Advani R, Chanan-Khan A, Switzky J, Liao QM, Shah D, Jewell RC, Lisby S, Lin TS. Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study. Lancet Haematol. 2017 Jan;4(1):e24-e34. Epub 2016 Nov 30. link to original article contains protocol PubMed

Panobinostat (Farydak)

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Regimen

Study Evidence
Ghobrial et al. 2013 Phase II

Chemotherapy

28-day cycles, given until progression of disease

References

  1. 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 PubMed

Rituximab (Rituxan)

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Regimen #1, "extended" course

Study Evidence
Treon et al. 2005 (WMCTG) Phase II, <20 pts in subgroup

Note: the abstract says that rituximab was given weeks 12 to 16 but this is likely a typo.

Chemotherapy

  • Rituximab (Rituxan) as follows:
    • Weeks 1 to 4: 375 mg/m2 IV once per week for four weeks
    • Weeks 12 to 15: 375 mg/m2 IV once per week for four weeks

One course (8 doses total)

Regimen #2, single course

Study Evidence
Gertz et al. 2004 (ECOG E3A98) Phase II

Chemotherapy

4-week course

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 PubMed
  2. 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
  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 contains verified protocol PubMed

RVR

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

Regimen

Study Evidence
Ghobrial et al. 2015 Phase I/II

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

Chemotherapy

28-day cycle for 6 cycles

Treatment was followed by everolimus maintenance.

References

  1. 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

Consolidation and/or maintenance after salvage therapy

Everolimus (Afinitor)

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Regimen

Study Evidence
Ghobrial et al. 2010 Phase II

Treatment preceded by RVR x 6.

Chemotherapy

Continued until progression

References

  1. 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

Response criteria