Skip to main content
Log in

Mantle cell lymphoma: established therapeutic options and future directions

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

During the last few years, new insights into the biology of mantle cell lymphoma have been obtained. However, with a median survival of only 3 years, mantle cell lymphoma remains the lymphoma subtype with the poorest prognosis. At initial diagnosis most patients present with advanced Ann Arbor stage III or IV and conventional chemotherapy hardly alters the continuously declining survival curve. Recently, two prospective randomized studies of the German Low Grade Lymphoma Study Group (GLSG) clearly confirmed the superiority of a combined immunochemotherapy. In a randomized study of the European mantle cell lymphoma Network, consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation improved the progression-free survival in patients younger than 65 years. However, relapses are still observed at a high frequency. Thus, new therapeutic strategies such as radioactively labeled antibodies or molecular targeting agents (e.g. Bortezomib or flavopiridol) are urgently warranted to further improve the clinical outcome of mantle cell lymphoma.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  1. Adkins D, Brown R, Goodnough LT, Khoury H, Popovic W, DiPersio J (1998) Treatment of resistant mantle cell lymphoma with allogeneic bone marrow transplantation. Bone Marrow Transplant 21:97–99

    Article  CAS  PubMed  Google Scholar 

  2. Andersen NS, Donovan JW, Borus JS, Poor CM, Neuberg D, Aster JC, Nadler LM, Freedman AS, Gribben JG (1997) Failure of immunologic purging in mantle cell lymphoma assessed by polymerase chain reaction detection of minimal residual disease. Blood 90:4212–4221

    CAS  PubMed  Google Scholar 

  3. Andersen NS, Jensen MK, de Nully Brown P, Geisler CH (2002) A Danish population-based analysis of 105 mantle cell lymphoma patients. Incidences, clinical features, response, survival and prognostic factors. Eur J Cancer 38:401–408

    Article  CAS  PubMed  Google Scholar 

  4. Banks PM, Chan J, Cleary ML, Delsol G, De Wolf-Peeters C, Gatter K, Grogan TM, Harris NL, Isaacson P, Jaffe ES (1992) Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol 16:637–640

    CAS  PubMed  Google Scholar 

  5. Berger F, Felman P, Sonet A, Salles G, Bastion Y, Bryon PA, Coiffier B (1994) Nonfollicular small B-cell lymphomas: a heterogeneous group of patients with distinct clinical features and outcome. Blood 83:2829–2835

    CAS  PubMed  Google Scholar 

  6. Bernard M, Gressin R, Lefrere F, Drenou B, Branger B, Caulet-Maugendre S, Tass P, Brousse N, Valensi F, Milpied N, Voilat L, Sadoun A, Ghandour C, Hunault M, Leloup R, Mannone L, Hermine O, Lamy T (2001) Blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype. Leukemia 15:1785–1791

    Article  CAS  PubMed  Google Scholar 

  7. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM (1994) Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. Embo J 13:2124–2130

    CAS  PubMed  Google Scholar 

  8. Bosch F, Lopez-Guillermo A, Campo E, Ribera JM, Conde E, Piris MA, Vallespi T, Woessner S, Montserrat E (1998) Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer 82:567–575

    Article  CAS  PubMed  Google Scholar 

  9. Campo E, Raffeld M, Jaffe ES (1999) Mantle-cell lymphoma. Semin Hematol 36:115–127

    CAS  PubMed  Google Scholar 

  10. Cohen BJ, Moskowitz C, Straus D, Noy A, Hedrick E, Zelenetz A (2001) Cyclophosphamide/fludarabine (CF) is active in the treatment of mantle cell lymphoma. Leuk Lymphoma 42:1015–1022

    CAS  PubMed  Google Scholar 

  11. Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Piva N, Milani R, Bullrich F, Veronese ML, Croce C, Birg F, Dohner H, Hagemeijer A, Castoldi G (1999) Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features. Blood 93:1372–1380

    CAS  PubMed  Google Scholar 

  12. Decaudin D, Bosq J, Tertian G, Nedellec G, Bennaceur A, Venuat AM, Bayle C, Carde P, Bendahmane B, Hayat M, Munck JN (1998) Phase II trial of fludarabine monophosphate in patients with mantle-cell lymphomas. J Clin Oncol 16:579–583

    CAS  PubMed  Google Scholar 

  13. Dreyling MH (2002) The increasing role of prognostic factors in the choice of treatment—Mantle Cell Lymphoma. Ann Oncol 13

  14. Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM (1995) A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 85:1075–1082

    CAS  PubMed  Google Scholar 

  15. Foran JM, Rohatiner AZ, Coiffier B, Barbui T, Johnson SA, Hiddemann W, Radford JA, Norton AJ, Tollerfield SM, Wilson MP, Lister TA (1999) Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenstrom's macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 17:546–553

    CAS  PubMed  Google Scholar 

  16. Foran JM, Rohatiner AZ, Cunningham D, Popescu RA, Solal-Celigny P, Ghielmini M, Coiffier B, Johnson PW, Gisselbrecht C, Reyes F, Radford JA, Bessell EM, Souleau B, Benzohra A, Lister TA (2000) European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 18:317–324

    CAS  PubMed  Google Scholar 

  17. Ghielmini M, Schmitz SF, Burki K, Pichert G, Betticher DC, Stupp R, Wernli M, Lohri A, Schmitter D, Bertoni F, Cerny T (2000) The effect of Rituximab on patients with follicular and mantle-cell lymphoma. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 11:123–126

    Article  Google Scholar 

  18. Gianni AM, Magni M, Martelli M, Di Nicola M, Carlo-Stella C, Pilotti S, Rambaldi A, Cortelazzo S, Patti C, Parvis G, Benedetti F, Capria S, Corradini P, Tarella C, Barbui T (2003) Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood 102:749–755

    Article  CAS  PubMed  Google Scholar 

  19. Gopal AK, Rajendran JG, Petersdorf SH, Maloney DG, Eary JF, Wood BL, Gooley TA, Bush SA, Durack LD, Martin PJ, Matthews DC, Appelbaum FR, Bernstein ID, Press OW (2002) High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 99:3158–3162

    CAS  PubMed  Google Scholar 

  20. Goy A, East K, Mesina O, Cabanillas F, Fayad L, Hagemeister F, McLaughlin P, Pro B, Romaguera J, Younes A, Wang M, Ford R, Gilles F, Scheinkein P, Trehu E, Rodriguez A (2003) Report of a phase II study of proteasome inhibitor Bortezomib in patients with relapsed or refractory indolent and aggressive B-cell lymphomas. Hematol J 4[Suppl 2]: 129

  21. Greiner TC, Moynihan MJ, Chan WC, Lytle DM, Pedersen A, Anderson JR, Weisenburger DD (1996) p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 87:4302–4310

    Google Scholar 

  22. Hernandez L, Fest T, Cazorla M, Teruya-Feldstein J, Bosch F, Peinado MA, Piris MA, Montserrat E, Cardesa A, Jaffe ES, Campo E, Raffeld M (1996) p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. Blood 87:3351–3359

    Google Scholar 

  23. Hiddemann W, Brittinger G, Tiemann M, Parwaresch R, Stein H, Lister TA, Norton AJ, Pittaluga S, De Wolf-Peeters C, Van Hoof A, Coiffier B, Berger F, Kluin-Nelemans JC, Van Krieken JH, Kluin PM, Cavalli F, Roggero E, Pedrinis E, Montserrat E, Piris MA, Unterhalt M (1996) Presentation features and clinical course of Mantle Cell Lymphomas—Results a European survey. Ann Oncol 7:22

    Google Scholar 

  24. Hiddemann W, Unterhalt M, Herrmann R, Woltjen HH, Kreuser ED, Trumper L, Reuss-Borst M, Terhardt-Kasten E, Busch M, Neubauer A, Kaiser U, Hanrath RD, Middeke H, Helm G, Freund M, Stein H, Tiemann M, Parwaresch R (1998) Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol 16:1922–1930

    CAS  PubMed  Google Scholar 

  25. Hiddemann W, Dreyling MH, Tiemann M, Schrader C, Unterhalt M (1999) Mantle cell lymphomas. Haematologica 84:93–95

    PubMed  Google Scholar 

  26. Hiddemann W, Dreyling MH, Pfreundschuh M, Gisselbrecht C, Diehl V, Boiron JM, Trümper L, Illiger H, Rudolph C, Boogaerts M, Kluin-Nelemans JC, Parwaresch R, Unterhalt M (2001) Myeloablative Radiochemotherapy followed by autologous Blood stem cell transplantation leads to a significant prolongation of the event-free survival in patients with mantle cell lymphoma (MCL) - results of a prospective randomized European Intergroup study. Blood 98

  27. Hiddemann W, Unterhalt M, Dreyling MH, Hossfeld DK, Lengfelder E, Metzner B, Pfreundschuh M, Kneba M, Fricke HJ, Boeck HP, Schmitz N, Koch P, Fuchs R (2002) The addition of Rituximab (R) to Combination Chemotherapy (CT) significantly improves the treatment of Mantle cell lymphoma (MCL): results of two prospective randomized studies by the German Low Grade Lymphoma Study Group (GLSG). Blood [Suppl, 44th annual meeting program and abstracts] 100:339

  28. Howard OM, Gribben JG, Neuberg DS, Grossbard M, Poor C, Janicek MJ, Shipp MA (2002) Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:1288–1294

    Article  CAS  PubMed  Google Scholar 

  29. Jaffe ES, Harris NL, Stein H, Vardiman J (2001) World Health Organisation classification of tumours: tumours of the haemopoitic and lymphoid tissues. IARC Press, Lyon

    Google Scholar 

  30. Kadayifci A, Benekli M, Savas MC, Arslan S, Uzunalimoglu B, Barista I, Gullu IH, Tekuzman G (1997) Multiple lymphomatous polyposis. J Surg Oncol 64:336–340

    Article  CAS  PubMed  Google Scholar 

  31. Khouri IF, Lee MS, Romaguera J, Mirza N, Kantarjian H, Korbling M, Albitar M, Giralt S, Samuels B, Anderlini P, Rodriguez J, von Wolff B, Gajewski J, Cabanillas F, Champlin R (1999) Allogeneic hematopoietic transplantation for mantle-cell lymphoma: molecular remissions and evidence of graft-versus-malignancy. Ann Oncol 10:1293–1299

    Article  CAS  PubMed  Google Scholar 

  32. Kouroukis CT, Belch A, Crump M, Eisenhauer E, Gascoyne RD, Meyer R, Lohmann R, Lopez P, Powers J, Turner R, Connors JM (2003) Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:1740–1745

    Article  PubMed  Google Scholar 

  33. Kroger N, Hoffknecht M, Kruger W, Zeller W, Renges H, Stute N, Zschaber R, Zander AR (2000) Allogeneic bone marrow transplantation for refractory mantle cell lymphoma. Ann Hematol 79:578–580

    Article  CAS  PubMed  Google Scholar 

  34. Lefrere F, Delmer A, Suzan F, Levy V, Belanger C, Djabarri M, Arnulf B, Damaj G, Maillard N, Ribrag V, Janvier M, Sebban C, Casasnovas RO, Bouabdallah R, Dreyfus F, Verkarre V, Delabesse E, Valensi F, McIntyre E, Brousse N, Varet B, Hermine O (2002) Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study. Leukemia 16:587–593

    Article  CAS  PubMed  Google Scholar 

  35. Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa RJ, Connors JM (2001) Limited stage mantle cell lymphoma: Clinical outcome in patients from British Columbia. Blood 98:1443

    Google Scholar 

  36. Lin TS, Howard OM, Neuberg DS, Kim HH, Shipp MA (2002) Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma. Leuk Lymphoma 43:793–797

    Article  CAS  PubMed  Google Scholar 

  37. Majlis A, Pugh WC, Rodriguez MA, Benedict WF, Cabanillas F (1997) Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants. J Clin Oncol 15:1664–1671

    CAS  PubMed  Google Scholar 

  38. Martinez C, Carreras E, Rovira M, Urbano-Ispizua A, Esteve J, Perales M, Fernandez F, Montserrat E (2000) Patients with mantle-cell lymphoma relapsing after autologous stem cell transplantation may be rescued by allogeneic transplantation. Bone Marrow Transplant 26:677–679

    Article  CAS  PubMed  Google Scholar 

  39. Meusers P, Engelhard M, Bartels H, Binder T, Fulle HH, Gorg K, Gunzer U, Havemann K, Kayser W, Konig E, et al (1989) Multicentre randomized therapeutic trial for advanced centrocytic lymphoma: anthracycline does not improve the prognosis. Hematol Oncol 7:365–380

    CAS  PubMed  Google Scholar 

  40. Meusers P, Hense J, Brittinger G (1997) Mantle cell lymphoma: diagnostic criteria, clinical aspects and therapeutic problems. Leukemia 11[Suppl 2]: S60–S64

  41. Morschhauser F, Marit G, Jourdan E, Solal-Celigny P, Fitoussi O, Wetterwald M, Rose C, Sebban C, Bouabdallah R, Kayitalire C, Dumontet C (2002) Gemcitabine with dexamethasone +/- cisplatin in patients with relapsing/refractory Mantle cell lymphoma. Blood [Suppl, 44th annual meeting program and abstracts] 100

  42. Norton AJ, Matthews J, Pappa V, Shamash J, Love S, Rohatiner AZ, Lister TA (1995) Mantle cell lymphoma: natural history defined in a serially biopsied population over a 20-year period. Ann Oncol 6:249–256

    CAS  PubMed  Google Scholar 

  43. Oinonen R, Franssila K, Elonen E (1999) Central nervous system involvement in patients with mantle cell lymphoma. Ann Hematol 78:145–149

    Article  CAS  PubMed  Google Scholar 

  44. Pham L, Tamayo A, Lo P, Yoshimura L, Ford RJ (2001) Anti-Tumor Activity of the Proteasome Inhibitor PS-341 in Mantle Cell Lymphoma B cells. Blood 98:465b

    Google Scholar 

  45. Pittaluga S, Wlodarska I, Stul MS, Thomas J, Verhoef G, Cassiman JJ, Van den Berghe H, de Wolf-Peeters C (1995) Mantle cell lymphoma: a clinicopathological study of 55 cases. Histopathology 26:17–24

    CAS  PubMed  Google Scholar 

  46. Romaguera JE, Khouri IF, Kantarjian HM, Hagemeister FB, Rodriguez MA, McLaughlin P, Sarris AH, Younes A, Rodriguez J, Cabanillas F (2000) Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma 39:77–85

    CAS  PubMed  Google Scholar 

  47. Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, Gascoyne RD, Grogan TM, Muller-Hermelink HK, Smeland EB, Chiorazzi M, Giltnane JM, Hurt EM, Zhao H, Averett L, Henrickson S, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Montserrat E, Bosch F, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Fisher RI, Miller TP, LeBlanc M, Ott G, Kvaloy S, Holte H, Delabie J, Staudt LM (2003) The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3:185–197

    CAS  PubMed  Google Scholar 

  48. Rummel M, Chow K, Karakas T, Jager E, Mezger J, von Grunhagen U, Schalk K, Burkhard O, Hansmann M, Ritzel H, Bergmann L, Hoelzer D, Mitrou P (2002) Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin's lymphoma. Eur J Cancer 38:1739

    Article  CAS  PubMed  Google Scholar 

  49. Samaha H, Dumontet C, Ketterer N, Moullet I, Thieblemont C, Bouafia F, Callet-Bauchu E, Felman P, Berger F, Salles G, Coiffier B (1998) Mantle cell lymphoma: a retrospective study of 121 cases. Leukemia 12:1281–7

    Article  CAS  PubMed  Google Scholar 

  50. Scheubner M, Huebler K, Ott G, Hiddemann W, Dreyling MH (2002) Genotyping of mantle cell lymphoma identifies a new tumor suppressor gene on 17p13.3. Ann Oncol 13:8

    Article  PubMed  Google Scholar 

  51. Seymour JF, Grigg AP, Szer J, Fox RM (2002) Cisplatin, fludarabine, and cytarabine: a novel, pharmacologically designed salvage therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin's lymphoma. Cancer 94:585–593

    Article  CAS  PubMed  Google Scholar 

  52. Sweetenham JW (2001) Stem cell transplantation for mantle cell lymphoma: should it ever be used outside clinical trials? Bone Marrow Transplant 28:813–820

    Article  CAS  PubMed  Google Scholar 

  53. Tarella C, Corradini P, Astolfi M, Bondesan P, Caracciolo D, Cherasco C, Ladetto M, Giaretta F, Ricca I, Vitolo U, Pileri A, Ferrero D (1999) Negative immunomagnetic ex vivo purging combined with high-dose chemotherapy with peripheral blood progenitor cell autograft in follicular lymphoma patients: evidence for long-term clinical and molecular remissions. Leukemia 13:1456–1462

    Article  CAS  PubMed  Google Scholar 

  54. Teodorovic I, Pittaluga S, Kluin-Nelemans JC, Meerwaldt JH, Hagenbeek A, van Glabbeke M, Somers R, Bijnens L, Noordijk EM, Peeters CD (1995) Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 13:2819–2826

    CAS  PubMed  Google Scholar 

  55. Tiemann M, Dreyling MH, et al (1999) Pathology, proliferation indices and survival in 304 patients. Ann Oncol 10

  56. Tobinai K (2002) Monoclonal antibody therapy for B-cell lymphoma: clinical trials of an anti-CD20 monoclonal antibody for B-cell lymphoma in Japan. Int J Hematol 76:411–419

    CAS  PubMed  Google Scholar 

  57. Vandenberghe E, De Wolf-Peeters C, Vaughan Hudson G, Vaughan Hudson B, Pittaluga S, Anderson L, Linch DC (1997) The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group. Br J Haematol 99:842–847

    CAS  PubMed  Google Scholar 

  58. Velders GA, Kluin-Nelemans JC, De Boer CJ, Hermans J, Noordijk EM, Schuuring E, Kramer MH, Van Deijk WA, Rahder JB, Kluin PM, Van Krieken JH (1996) Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol 14:1269–1274

    CAS  PubMed  Google Scholar 

  59. Walsh SH, Thorselius M, Johnson A, Soderberg O, Jerkeman M, Bjorck E, Eriksson I, Thunberg U, Landgren O, Ehinger M, Lofvenberg E, Wallman K, Enblad G, Sander B, Porwit-MacDonald A, Dictor M, Olofsson T, Sundstrom C, Roos G, Rosenquist R (2003) Mutated VH genes and preferential VH3–21 use define new subsets of mantle cell lymphoma. Blood 101:4047–4054

    Article  CAS  PubMed  Google Scholar 

  60. Weisenburger DD, Armitage JO (1996) Mantle cell lymphoma—an entity comes of age. Blood 87:4483–4494

    CAS  PubMed  Google Scholar 

  61. Weisenburger DD, Vose JM, Greiner TC, Lynch JC, Chan WC, Bierman PJ, Dave BJ, Sanger WG, Armitage JO (2000) Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. Am J Hematol 64:190–196

    Article  CAS  PubMed  Google Scholar 

  62. Wlodarska I, Pittaluga S, Hagemeijer A, De Wolf-Peeters C, Van Den Berghe H (1999) Secondary chromosome changes in mantle cell lymphoma. Haematologica 84:594–599

    CAS  PubMed  Google Scholar 

  63. Zoldan MC, Inghirami G, Masuda Y, Vandekerckhove F, Raphael B, Amorosi E, Hymes K, Frizzera G (1996) Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome. Br J Haematol 93:475–486

    CAS  PubMed  Google Scholar 

  64. Zucca E, Roggero E, Pinotti G, Pedrinis E, Cappella C, Venco A, Cavalli F (1995) Patterns of survival in mantle cell lymphoma. Ann Oncol 6:257–262

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G. Lenz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lenz, G., Dreyling, M. & Hiddemann, W. Mantle cell lymphoma: established therapeutic options and future directions. Ann Hematol 83, 71–77 (2004). https://doi.org/10.1007/s00277-003-0774-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-003-0774-2

Keywords

Navigation