Skip to main content

Advertisement

SpringerLink
Log in

Mantle cell lymphoma: Evolving novel options

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Mantle cell lymphoma (MCL) represents only 6% of non-Hodgkin’s lymphoma but is one of the most active fields of clinical investigation. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and rituximab. Unfortunately, no standard therapy has been defined, and most patients eventually relapse. An impressive number of novel agents are currently being tested, the bulk of which are biologic agents or targeted therapies. Bortezomib is the first in class of proteasome inhibitors and the first new agent to be approved in relapsed/refractory MCL. Other small molecules have shown encouraging activity, including mTOR and Bcl-2 inhibitors, novel antibodies, and new cytotoxic agents. Future trials will also benefit from new molecular approaches through pharmacogenomics.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Fu K, Weisenburger DD, Greiner TC, et al.: Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood 2005, 106:4315–4321.

    Article  PubMed  CAS  Google Scholar 

  2. Fernandez V, Hartmann E, Ott G, et al.: Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol 2005, 23:6364–6369.

    Article  PubMed  CAS  Google Scholar 

  3. Kohlhammer H, Schwaenen C, Wessendorf S, et al.: Genomic DNA-chip hybridization in t(11, 14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions. Blood 2004, 104:795–801.

    Article  PubMed  CAS  Google Scholar 

  4. Rosenwald A, Wright G, Wiestner A, et al.: The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 2003, 3:185–197.

    Article  PubMed  CAS  Google Scholar 

  5. Katzenberger T, Petzoldt C, Holler S, et al.: The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood 2006, 107:3407.

    Article  PubMed  CAS  Google Scholar 

  6. Schlette E, Lai R, Onciu M, et al.: Leukemic mantle cell lymphoma: clinical and pathologic spectrum of twenty-three cases. Mod Pathol 2001, 14:1133–1140.

    Article  PubMed  CAS  Google Scholar 

  7. Pott C, Schrader C, Gesk S, et al.: Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantation predicts long-term remission in mantle cell lymphoma. Blood 2006, 107:2271–2278.

    Article  PubMed  CAS  Google Scholar 

  8. Kienle D, Krober A, Katzenberger T, et al.: VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome. Blood 2003, 102:3003–3009.

    Article  PubMed  CAS  Google Scholar 

  9. Hoster E, Dreyling N, Unterhalt M, et al.: A new prognostic index (MIPI) for patients with advanced stage mantle cell lymphoma. Blood 2006, 108:814.

    Google Scholar 

  10. Armitage JO: Management of mantle cell lymphoma. Oncology (Williston Park) 1998, 12:49–55.

    CAS  Google Scholar 

  11. Romaguera JE, Medeiros LJ, Hagemeister FB, et al.: Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer 2003, 97:586–591.

    Article  PubMed  Google Scholar 

  12. Howard OM, Gribben JG, Neuberg DS, et al.: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J. Clin Oncol 2002, 20:1288–1294.

    Article  PubMed  CAS  Google Scholar 

  13. Khouri IF, Romaguera J, Kantarjian H, et al.: Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 1998, 16:3803–3809.

    PubMed  CAS  Google Scholar 

  14. Romaguera JE, Fayad L, Rodriguez MA, et al.: High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 2005, 23:7013–7023.

    Article  PubMed  CAS  Google Scholar 

  15. Kahl BS, McGovern, Blank J, et al.: Phase II study of modified hyper-CVAD with rituximab maintenance for previously untreated mantle cell lymphoma: A Wisconsin Oncology Network Study [abstract]. Blood 2004, 104:1388.

    Google Scholar 

  16. Decaudin D, Bosq J, Tertian G, et al.: Phase II trial of fludarabine monophosphate in patients with mantle-cell lymphomas. J Clin Oncol 1998, 16:579–583.

    PubMed  CAS  Google Scholar 

  17. Cohen BJ, Moskowitz C, Straus D, et al.: Cyclophosphamide/fludarabine (CF) is active in the treatment of mantle cell lymphoma. Leuk Lymphoma 2001, 42:1015–1022.

    Article  PubMed  CAS  Google Scholar 

  18. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004, 104:3064–3071.

    Article  PubMed  CAS  Google Scholar 

  19. Ritchie DS, Seymour JF, Grigg AP, et al.: The hyper-CVAD-rituximab chemotherapy programme followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma. Ann Hematol 2007, 86:101–105.

    Article  PubMed  CAS  Google Scholar 

  20. Lefrere F, Delmer A, Suzan F, et al.: 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 2002, 16:587–593.

    Article  PubMed  CAS  Google Scholar 

  21. Khouri IF, Lee MS, Saliba RM, et al.: Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol 2003, 21:4407–4412.

    Article  PubMed  CAS  Google Scholar 

  22. Rummel MJ, Al-Batran SE, Kim SZ, et al.: 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, 23:3383–3389.

    Article  PubMed  CAS  Google Scholar 

  23. Zelenetz A, Noy A, Pandit-Taskar M, et al.: Sequential radioimmunotherapy with tositumomab/iodine I131 tositumomab followed by CHOP for mantle cell lymphoma demonstrates RIT can induce molecular remissions [abstract]. J Clin Oncol Proc ASCO 2006, 24:7560

    Google Scholar 

  24. Smith M, Chen H, Gordon L, Horning S: Phase II study of rituximab + CHOP followed by 90Y-ibritumomab tiuxetan in patents with previously untreated mantle cell lymphoma: An Eastern Cooperative Oncology Group Study (E1499) [abstract]. J Clin Oncol 2006, 24:7503.

    Google Scholar 

  25. Oki Y, Pro B, Depassand E, et al.: A phase II study of yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin) for treatment of patients with relapsed and refractory mantle cell lymphoma (MCL) [abstract]. Blood 2004, 104:2632.

    Google Scholar 

  26. Gopal AK, Rajendran JG, Petersdorf SH, et al.: High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 2002, 99:3158–3162.

    Article  PubMed  CAS  Google Scholar 

  27. Morschhauser F, Leonard JP, Fayad L, et al.: Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results [abstract]. J Clin Oncol 2007, 25:8032.

    Google Scholar 

  28. Advani A, Giné E, Gisselbrecht C, et al.: Preliminary report of a phase 1 study of CMC-544, an antibody-targeted chemotherapy agent, in patients with B-cell non-Hodgkin’s lymphoma (NHL) [abstract]. Blood 2005, 106:230.

    Google Scholar 

  29. Advani R, Furman R, Rosenblatt J, et al.: A phase I study of humanized anti-CD40 immunotherapy with SGN-40 in non-Hodgkin’s lymphoma [abstract]. Blood 2005, 108:1504.

    Google Scholar 

  30. Younes Y, Vose J, Zelenetz A, et al.: Results of a phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory non-Hodgkin’s lymphoma (NHL) [abstract]. Blood 2005, 106:489.

    Google Scholar 

  31. Neelapu SS, Kwak LW, Kobrin CB, et al.: Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med 2005, 11:986–991.

    PubMed  CAS  Google Scholar 

  32. Peggs KS, Quezada SA, Korman AJ, Allison JP: Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 2006, 18:206–213.

    Article  PubMed  CAS  Google Scholar 

  33. Adams J: The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004, 4:349–360.

    Article  PubMed  CAS  Google Scholar 

  34. Goy A, East K, Mesina F, et al.: Report of a phase II study of proteasome inhibitor bortezomib in patients with relapsed or refractory indolent and aggressive B-cell lymphomas [abstract]. J Clin Oncol Proc ASCO 2003, 22:2291.

    Google Scholar 

  35. O’Connor OA, Wright J, Moskowitz C, et al.: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 2005, 23:676–684.

    Article  PubMed  CAS  Google Scholar 

  36. Strauss S, Maharaj L, Jim Stec J, et al.: Phase II clinical study of bortezomib (VELCADE®) in patients (pts) with relapsed / refractory non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD) [abstract]. Blood 2004, 104:1386.

    Article  CAS  Google Scholar 

  37. Belch A, Kouroukis C, Crump M, et al.: Phase II trial of bortezomib in mantle cell lymphoma [abstract]. Oral Session. Blood 2004, 104:608.

    Google Scholar 

  38. Goy A, Bernstein S, Kahl BS, et al.: Bortezomib in relapsed or refractory mantle cell lymphoma (MCL): results of the PINNACLE study [abstract]. J Clin Oncol Proc ASCO 2006, 24:7512.

    Google Scholar 

  39. Fisher RI, Bernstein S, Kahl BS, et al.: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006, 24:4867–4874.

    Article  PubMed  Google Scholar 

  40. Goy A, Remache Y, Barkoh, et al.: Sensitivity, schedule-dependence and molecular effects of the proteasome inhibitor bortezomib in non-Hodgkin’s lymphoma cells [abstract]. Blood 2004, 104:389a.

    Google Scholar 

  41. Goy A, Younes A, McLaughlin P, et al.: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2005, 23:667–675.

    Article  PubMed  CAS  Google Scholar 

  42. Richardson PG, Briemberg H, Jagannath S, et al.: Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 2006, 24:3113–3120.

    Article  PubMed  CAS  Google Scholar 

  43. Gerecitano J, Goy A, Wright J, et al.: Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: a possible surrogate marker of response? Br J Haematol 2006, 134:391–398.

    Article  PubMed  CAS  Google Scholar 

  44. De Vos S, Dakhil SR, McLaughlin P, et al.: Phase 2 study of bortezomib weekly or twice weekly plus rituximab in patients with follicular (FL) or marginal zone (MZL) lymphoma: final results. Oral Session. Blood 2006; 108.

  45. O’Connor O, Hamlin P, Moskowitz C, et al.: Schedule of bortezomib administration may be an important determinant of single-agent activity in patients with relapsed or refractory follicular (FL) lymphoma and mantle cell lymphoma (MCL). J Clin Oncol 2007, 25:8051.

    Google Scholar 

  46. Weigert O, Pastore A, Rieken M, et al.: Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma. Leukemia 2007, 21:524–528.

    Article  PubMed  CAS  Google Scholar 

  47. Drach J, Kaufmann H, Pichelmayer O, et al.: Marked activity of bortezomib, rituximab, and dexamethasone (BORID) in heavily pretreated patients with mantle cell lymphoma. J Clin Oncol 2006, 24:17522.

    Google Scholar 

  48. Leonard J, Furman R, Feldman E, et al.: Phase I/II trial of bortezomib + CHOP-rituximab in diffuse large B cell (DLBCL) and mantle cell lymphoma (MCL): phase I results [abstract]. Blood 2005, 104:491.

    Google Scholar 

  49. Mounier N, Ribrag V, Haioun C, et al.: Efficacy and toxicity of two schedules of R-CHOP plus bortezomib in front-line B lymphoma patients: A randomized phase II trial from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) [abstract]. J Clin Oncol 2007, 25:8010.

    Google Scholar 

  50. Stewart KA, O’Connor OA, Alsina M, et al.: Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: responses in multiple myeloma and Waldenstrom’s macroglobulinemia at well-tolerated doses. J Clin Oncol 2007, 25:8003.

    Article  CAS  Google Scholar 

  51. Witzig TE, Geyer SM, Ghobrial I, et al.: Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005, 23:5347–5356.

    Article  PubMed  CAS  Google Scholar 

  52. Rudelius M, Pittaluga S, Nishizuka S, et al.: Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 2006, 108:1668–1676.

    Article  PubMed  CAS  Google Scholar 

  53. Yee KW, Zeng Z, Konopleva M, et al.: Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006, 12:5165–5173.

    Article  PubMed  CAS  Google Scholar 

  54. Feldman E, Giles F, Roboz G, et al.: A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol 2005, 23:6631.

    Article  CAS  Google Scholar 

  55. Kaufmann H, Raderer M, Wohrer S, et al.: Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood 2004, 104:2269–2271.

    Article  PubMed  CAS  Google Scholar 

  56. Witzig TE, Vose JM, Kaplan HP, et al.: Early results from a phase II study of lenalidomide monotherapy in relapsed/refractory indolent non-Hodgkin’s lymphoma. Blood 2006, 108:2482.

    Google Scholar 

  57. Wang M, Fayad L, Hagemeister F, et al.: A phase I/II study of lenalidomide (Len) in combination with rituximab (R) in relapsed/refractory mantle cell lymphoma (MCL) with early evidence of efficacy. J Clin Oncol 2007, 25:8030.

    Article  Google Scholar 

  58. Younes A, Fanale M, Pro B, et al.: A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma. J Clin Oncology 2007, 25:8000.

    Google Scholar 

  59. O’Connor OA, Heaney ML, Schwartz L, et al.: Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006, 24:166–173.

    Article  PubMed  CAS  Google Scholar 

  60. Heider U, Kaiser M, Sterz J, et al.: Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma. Eur J Haematol 2006, 76:42–50.

    Article  PubMed  CAS  Google Scholar 

  61. Perez-Galan P, Roue G, Villamor N, et al.: The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 2007, 109:4441–4449.

    Article  PubMed  CAS  Google Scholar 

  62. Kouroukis CT, Belch A, Crump M, et al.: 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 2003, 21:1740–1745.

    Article  PubMed  CAS  Google Scholar 

  63. Byrd JC, Lin TS, Dalton JT, et al.: Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007, 109:399–404.

    Article  PubMed  CAS  Google Scholar 

  64. Lin TS, Fischer B, Moran M, et al.: Flavopiridol, fludarabine and rituximab is a highly active regimen in indolent B-cell lymphoproliferative disorders including mantle cell lymphoma. Blood 2005, 106:944.

    Google Scholar 

  65. Robertson MJ, Kahl BS, Vose JM, et al.: Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2007, 25:1741–1746.

    Article  PubMed  CAS  Google Scholar 

  66. Pham LV, Tamayo AT, Yoshimura LC, et al.: Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 2003, 171:88–95.

    PubMed  CAS  Google Scholar 

  67. Chauhan D, Li G, Shringarpure R, et al.: Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003, 63:6174–6177.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lymphoma Division, Hackensack Medical University Cancer Center, 20 Prospect Avenue, Hackensack, NJ, 07601, USA

    Andre Goy MD

Authors
  1. Andre Goy MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andre Goy MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goy, A. Mantle cell lymphoma: Evolving novel options. Curr Oncol Rep 9, 391–398 (2007). https://doi.org/10.1007/s11912-007-0053-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-007-0053-9

Keywords

Search

Navigation