Skip to main content
SpringerLink
Log in

Biology, Prognosis, and Therapy of Waldenström Macroglobulinemia

  • Chapter
  • First Online:
Non-Hodgkin Lymphoma

Part of the book series: Cancer Treatment and Research ((CTAR,volume 165))

Abstract

Waldenström Macroglobulinemia (WM) is a rare B-cell lymphoma characterized by the uncontrolled accumulation of malignant lymphoplasmacytic cells, mainly in the bone marrow, and monoclonal IgM production. Despite its rarity, our understanding of the biology of this disease has improved significantly in recent years with the identification of recurrent mutations in the MYD88 and CXCR4 genes. Based on the diversity of clinical features observed in WM patients, therapy should be highly personalized having into account several factors such as age, co-morbidities, IgM levels, and presence of hyperviscosity, coagulopathy, cryoglobulinemia, or cold agglutinin disease. In this chapter, we review the recent advances in the biology of WM and the current therapeutic options for untreated and relapsed WM patients. Finally, we discuss the role of prognostic factors and current evidence supporting an improvement in the survival of WM patients in the last decade.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Swerdlow SH, Berger F, Pileri SA et al (2008) Lymphoplasmacytic lymphoma. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France, IARC, pp 194–195

    Google Scholar 

  2. Treon SP, Hunter ZR, Aggarwal A et al (2006) Characterization of familial waldenstrom’s macroglobulinemia. Ann Oncol 17:488–494

    Article  CAS  PubMed  Google Scholar 

  3. Ciccarelli BT, Patterson CJ, Hunter ZR et al (2011) Hepcidin is produced by lymphoplasmacytic cells and is associated with anemia in waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk 11:160–163

    Article  CAS  PubMed  Google Scholar 

  4. Schop RF, Kuehl WM, Van Wier SA, Ahmann GJ, Price-Troska T, Bailey RJ, Jalal SM, Qi Y, Kyle RA, Greipp PR, Fonseca R (2002) Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 100(8):2996–3001.

    Google Scholar 

  5. Treon SP, Xu L, Yang G et al (2012) MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med 367:826–833

    Article  CAS  PubMed  Google Scholar 

  6. Jimenez C, Sebastian E, Chillon MC et al (2013) MYD88 L265P is a marker highly characteristic of, but not restricted to waldenstrom’s macroglobulinemia. Leukemia 27:1722–1728

    Article  CAS  PubMed  Google Scholar 

  7. Mori N, Ohwashi M, Yoshinaga K et al (2013) L265P mutation of the MYD88 gene is frequent in waldenstrom’s macroglobulinemia and its absence in myeloma. PLoS one 8:80088

    Article  Google Scholar 

  8. Poulain S, Roumier C, Decambron A et al (2013) MYD88 L265P mutation in Waldenstrom macroglobulinemia. Blood 121:4504–4511

    Article  CAS  PubMed  Google Scholar 

  9. Varettoni M, Arcaini L, Zibellini S et al (2013) Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom’s macroglobulinemia and related lymphoid neoplasms. Blood 121:2522–2528

    Article  CAS  PubMed  Google Scholar 

  10. Yang G, Zhou Y, Liu X et al (2013) A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia. Blood 122:1222–1232

    Article  CAS  PubMed  Google Scholar 

  11. Watters TM, Kenny EF, O’Neill LA (2007) Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunol Cell Biol 85:411–419

    Article  CAS  PubMed  Google Scholar 

  12. Lin SC, Lo YC, Wu H (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465:885–890

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kawagoe T, Sato S, Matsushita K et al (2008) Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 9:684–691

    Article  CAS  PubMed  Google Scholar 

  14. Hunter ZR, Xu L, Yang G et al (2014) The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 123:1637–1646

    Article  CAS  PubMed  Google Scholar 

  15. Busillo JM, Benovic JL (2007) Regulation of CXCR4 signaling. Biochim Biophys Acta 1768:952–963

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Treon SP, Cao Y, Xu L et al (2014) Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 123:2791–2796

    Article  CAS  PubMed  Google Scholar 

  17. Roccaro AM, Sacco A, Jimenez C, Maiso P, Moschetta M, Mishima Y, Aljawai Y, Sahin I, Kuhne M, Cardarelli P, Cohen L, San Miguel JF, Garcia-Sanz R, Ghobrial IM (2014) C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 123(26):4120–4131

    Google Scholar 

  18. Kyle RA, Treon SP, Alexanian R et al (2003) Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the second international workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 30:116–120

    Article  PubMed  Google Scholar 

  19. NCCN Clinical Practices Guidelines in Oncology (NCCN Guidelines). Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma. Available at http://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf. Accessed 1 June 2014

  20. Treon SP, Ioakimidis L, Soumerai JD et al (2009) Primary therapy of Waldenstrom macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol 27:3830–3835

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Ghobrial IM, Xie W, Padmanabhan S et al (2010) Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenstrom macroglobulinemia. Am J Hematol 85:670–674

    Article  CAS  PubMed  Google Scholar 

  22. Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M et al (2013) Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood 122:3276–3282

    Article  CAS  PubMed  Google Scholar 

  23. Moreau P, Pylypenko H, Grosicki S et al (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12:431–440

    Article  PubMed  Google Scholar 

  24. 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 (2014) Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood 124(4):503–510

    Google Scholar 

  25. Treon SP (2009) How I treat Waldenstrom macroglobulinemia. Blood 114:2375–2385

    Article  CAS  PubMed  Google Scholar 

  26. Ioakimidis L, Patterson CJ, Hunter ZR et al (2009) Comparative outcomes following CP-R, CVP-R, and CHOP-R in waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma 9:62–66

    Article  CAS  PubMed  Google Scholar 

  27. Rummel MJ, Niederle N, Maschmeyer G et al (2013) 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 381:1203–1210

    Article  CAS  PubMed  Google Scholar 

  28. Leblond V, Johnson S, Chevret S et al (2013) Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated Waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol 31:301–307

    Article  CAS  PubMed  Google Scholar 

  29. Treon SP, Branagan AR, Ioakimidis L et al (2009) Long-term outcomes to fludarabine and rituximab in Waldenstrom macroglobulinemia. Blood 113:3673–3678

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Tedeschi A, Benevolo G, Varettoni M et al (2012) Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer 118:434–443

    Article  CAS  PubMed  Google Scholar 

  31. Treon SP, Soumerai JD, Branagan AR et al (2008) Thalidomide and rituximab in Waldenstrom macroglobulinemia. Blood 112:4452–4457

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Gertz MA, Rue M, Blood E et al (2004) Multicenter phase 2 trial of rituximab for Waldenstrom macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma 45:2047–2055

    Article  CAS  PubMed  Google Scholar 

  33. Treon SP, Emmanouilides C, Kimby E et al (2005) Extended rituximab therapy in waldenstrom’s macroglobulinemia. Ann Oncol 16:132–138

    Article  CAS  PubMed  Google Scholar 

  34. Treon SP, Branagan AR, Hunter Z et al (2004) Paradoxical increases in serum IgM and viscosity levels following rituximab in waldenstrom’s macroglobulinemia. Ann Oncol 15:1481–1483

    Article  CAS  PubMed  Google Scholar 

  35. Chen C, Kouroukis CT, White D et al (2009) Bortezomib in relapsed or refractory waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma 9:74–76

    Article  CAS  PubMed  Google Scholar 

  36. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC et al (2005) Treatment of relapsed or refractory waldenstrom’s macroglobulinemia with bortezomib. Haematologica 90:1655–1658

    CAS  PubMed  Google Scholar 

  37. Ghobrial IM, Hong F, Padmanabhan S et al (2010) Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol 28:1422–1428

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Treon SP, Hunter ZR, Matous J et al (2007) Multicenter clinical trial of bortezomib in relapsed/refractory waldenstrom’s macroglobulinemia: results of WMCTG Trial 03-248. Clin Cancer Res 13:3320–3325

    Article  CAS  PubMed  Google Scholar 

  39. Zinzani PL, Gherlinzoni F, Bendandi M et al (1995) Fludarabine treatment in resistant waldenstrom’s macroglobulinemia. Eur J Haematol 54:120–123

    Article  CAS  PubMed  Google Scholar 

  40. Treon SP, Hanzis C, Tripsas C et al (2011) Bendamustine therapy in patients with relapsed or refractory waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk 11:133–135

    Article  CAS  PubMed  Google Scholar 

  41. Furman RR, Eradat H, DiRienzo CG et al (2011) A phase II trial of ofatumumab in subjects with Waldenstrom’s macroglobulinemia. ASH Annu Meet Abstr 118:3701

    Google Scholar 

  42. Ghobrial IM, Gertz M, Laplant B et al (2010) Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol 28:1408–1414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Treon SP, Tripsas CK, Ioakimidis L et al (2011) Prospective, multicenter study of the MTOR inhibitor everolimus (RAD001) as primary therapy in Waldenstrom’s macroglobulinemia. ASH Annu Meet Abstr 118:2951

    Google Scholar 

  44. Treon SP, Tripsas CK, Yang G et al (2013) A prospective multicenter study of the Bruton’s tyrosine kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenstrom’s macroglobulinemia. Blood 122:251

    Article  Google Scholar 

  45. Treon SP, Hanzis C, Manning RJ et al (2011) Maintenance rituximab is associated with improved clinical outcome in rituximab naive patients with Waldenstrom macroglobulinaemia who respond to a rituximab-containing regimen. Br J Haematol 154:357–362

    Article  CAS  PubMed  Google Scholar 

  46. Rummel MJ, Lerchenmuller C, Greil R et al (2012) 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 Ann Meet Abstr 120:2739

    Google Scholar 

  47. Kyriakou C, Canals C, Sibon D et al (2010) High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the lymphoma working party of the european group for blood and marrow transplantation. J Clin Oncol 28:2227–2232

    Article  CAS  PubMed  Google Scholar 

  48. Kyriakou C, Canals C, Cornelissen JJ et al (2010) Allogeneic stem-cell transplantation in patients with Waldenstrom macroglobulinemia: report from the lymphoma working party of the european group for blood and marrow transplantation. J Clin Oncol 28:4926–4934

    Article  PubMed  Google Scholar 

  49. Morel P, Duhamel A, Gobbi P et al (2009) International prognostic scoring system for Waldenstrom macroglobulinemia. Blood 113:4163–4170

    Article  CAS  PubMed  Google Scholar 

  50. Treon SP, Yang G, Hanzis C et al (2011) Attainment of complete/very good partial response following rituximab-based therapy is an important determinant to progression-free survival, and is impacted by polymorphisms in FCGR3A in Waldenstrom macroglobulinaemia. Br J Haematol 154:223–228

    Article  PubMed  Google Scholar 

  51. Kastritis E, Kyrtsonis MC, Hatjiharissi E et al (2011) No significant improvement in the outcome of patients with waldenstrom’s macroglobulinemia treated over the last 25 years. Am J Hematol 86:479–483

    Article  PubMed  Google Scholar 

  52. Kristinsson SY, Eloranta S, Dickman PW et al (2013) Patterns of survival in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: a population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005. Am J Hematol 88:60–65

    Article  PubMed  Google Scholar 

  53. Castillo JJ, Olszewski AJ, Cronin AM et al (2014) Survival trends in Waldenstrom macroglobulinemia: an analysis of the surveillance, epidemiology and end results database. Blood 123:3999–4000

    Article  CAS  PubMed  Google Scholar 

  54. Shenoy PJ, Malik N, Nooka A et al (2011) Racial differences in the presentation and outcomes of diffuse large B-cell lymphoma in the United States. Cancer 117:2530–2540

    Article  PubMed  Google Scholar 

  55. Shenoy P, Maggioncalda A, Malik N, Flowers CR (2011) Incidence patterns and outcomes for hodgkin lymphoma patients in the United States. Adv Hematol 2011:725219

    PubMed Central  PubMed  Google Scholar 

  56. Nabhan C, Aschebrook-Kilfoy B, Chiu BC et al. (2014) The impact of race, ethnicity, age, and sex on clinical outcome in chronic lymphocytic leukemia: a comprehensive SEER analysis in the modern era. Leuk Lymphoma 2014

    Google Scholar 

  57. Nabhan C, Aschebrook-Kilfoy B, Chiu BC et al. (2014) The impact of race, age, and sex in follicular lymphoma: a comprehensive SEER analysis across consecutive treatment eras. Am J Hematol, 89(6): 633–638

    Google Scholar 

  58. Castillo JJ, Winer ES, Olszewski AJ (2013) Population-based prognostic factors for survival in patients with burkitt lymphoma: an analysis from the surveillance, epidemiology, and end results database. Cancer 119:3672–3679

    PubMed  Google Scholar 

  59. Gopal AK, Kahl BS, de Vos S et al (2014) PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008–1018

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Flinn IW, Kahl BS, Furman RR et al (2014) Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 123:3406–3413

    Article  CAS  PubMed  Google Scholar 

  61. Davids SM, Seymour JF, Gerecitano JF et al (2014) Phase I study of ABT-199 (GDC-199) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol 32:8522

    Google Scholar 

  62. Dhodapkar MV, Hoering A, Gertz MA, Rivkin S, Szymonifka J, Crowley J, Barlogie B (2009) Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood 113(4):793–796

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, M221, 02215, Boston, MA, USA

    Jorge J. Castillo, Irene M. Ghobrial & Steven P. Treon

Authors
  1. Jorge J. Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene M. Ghobrial
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven P. Treon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jorge J. Castillo .

Editor information

Editors and Affiliations

  1. Division of Hematology/Oncology, Tufts Medical Center, Boston, Massachusetts, USA

    Andrew M. Evens

  2. Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA

    Kristie A. Blum

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Castillo, J.J., Ghobrial, I.M., Treon, S.P. (2015). Biology, Prognosis, and Therapy of Waldenström Macroglobulinemia. In: Evens, A., Blum, K. (eds) Non-Hodgkin Lymphoma. Cancer Treatment and Research, vol 165. Springer, Cham. https://doi.org/10.1007/978-3-319-13150-4_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-13150-4_7

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-13149-8

  • Online ISBN: 978-3-319-13150-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation