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International Journal of Hematology

, Volume 105, Issue 3, pp 257–264 | Cite as

Current treatment strategies in relapsed/refractory mantle cell lymphoma: where are we now?

  • Erden Atilla
  • Pinar Ataca Atilla
  • Taner DemirerEmail author
Review Article

Abstract

The management of relapsed/refractory mantle cell lymphoma remains challenging. Patients with relapsed mantle cell lymphoma have been treated with multi-agent salvage chemotherapies; however, outcomes are poor. Although there have been studies in the relapse/refractory setting, current data indicate that autologous hematopoietic stem cell transplantation may be an especially useful approach in the front line setting in patients in first complete or partial remission following induction chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only curative option, although reduced intensity conditioning in chemo-sensitive relapse or refractory mantle cell lymphoma provides better survival rates. In addition, bortezomib, lenalidomide, temsirolimus, and ibrutinib have opened a new therapeutic era. More randomized trials should be conducted to evaluate the appropriate use of these new molecules. In this review, I discuss autologous and allo-transplant options as well as the data regarding recently approved novel agents in the relapse/refractory setting in patients with MCL.

Keywords

Mantle cell lymphoma Relapsed Refractory 

Notes

Compliance with ethical standards

Conflict of interest

None.

References

  1. 1.
    Zhou Y, Wang H, Fang W, Romaguer J, Zhang Y, Delasalle KB, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer. 2008;113:791–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Samad N, Younes A. Temsirolimus in the treatment of relapse refractory mantle cell lymphoma. Onco Targets Ther. 2010;3:167–78.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, et al. Improvement of overall survival in advanced stage Mantle Cell Lymphoma. J Clin Oncol. 2009;27:511–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111:558–65.CrossRefPubMedGoogle Scholar
  5. 5.
    Robinson S, Dreger P, Caballero D, Corradini P, Geisler C, Ghielmini M, et al. The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma. Leukemia. 2015;29:464–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Dreyling MH, Lenz G, Schiegnitz E, van Hoof A, Gisselbrecht C, Pfreundschuh M, et al. Early consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle cell lymphoma—Long term follow up of a prospective randomized trial. Blood. 2005;104:6A.Google Scholar
  7. 7.
    Bernstein SH, Epner E, Unger JM. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Br J Haematol. 2010;150:200–8.Google Scholar
  8. 8.
    Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Kenkre VP, Long WL, Eickhoff JC, Blank JH, McFarland TA, Bottner W, et al. Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma:long-term follow-up of a pilot study from the Wisconsin Oncology Network. Leuk Lymphoma. 2011;52:1675–80.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Barista I, Romaguera JE, Cabanillas F. Mantle cell lymphoma. Lancet Oncol. 2001;2:141–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Dietrich S, Boumendil A, Finel H, Avivi I, Volin L, Cornelissen J, et al. Outcome and prognostic factors in patients with mantle-cell lymphoma relapsing after autologous stem-cell transplantation:a retrospective study of the European Group for Blood and Marrow Transplantation (EMBT). Ann Oncol. 2014;25:1053–8.CrossRefPubMedGoogle Scholar
  12. 12.
    De Giorgi U, Rosti G, Slavin S, Yaniv I, Harousseau JL, Landenstein R, et al. Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer. 2005;93(4):412–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pedrazzoli P, Ledermann JA, Lotz JP, Leyvraz S, Aglietta M, Rosti G, European Group Blood Marrow Transplantation, et al. High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults. Ann Oncol. 2006;17(10):1479–88.CrossRefPubMedGoogle Scholar
  14. 14.
    Berry DA, Donald A, Ueno NT, Johnson MM, Lei X, Smith DA, et al. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation in metastatic breast cancer: overview of six randomized trials. J Clin Oncol. 2011;29(24):3224–31.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Demirer T, Celebi H, Arat M, Ustun C, Demirer S, Dilek I, et al. Autoimmune thrombocytopenia in a patient with small cell lung cancer developing after chemotherapy and resolving following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1999;24(3):335–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Pedrazzoli P, Ferrante P, Kulekci A, Schiavo R, De Giorgi U, Carminati O, et al. Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990–1999. Bone Marrow Transplant. 2003;32(5):489–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Demirer T, Petersen FB, Bensinger WI, Appelbaum FR, Fefer A, Rowley S, et al. Autologous transplantation with peripheral blood stem cells collected after granulocyte colony-stimulating factor in patients with acute myelogenous leukemia. Bone Marrow Transplant. 1996;18(1):29–34.PubMedGoogle Scholar
  18. 18.
    Kroger N, Damon L, Zander AR, Wandt H, Derigs G, Ferrante P, et al. Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients. Bone Marrow Transplant. 2003;32(12):1153–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Fenske TS, Zhang MJ, Carreras J, Ayala E, Burns LJ, Cashen A, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. J Clin Oncol. 2014;32:273–81.CrossRefPubMedGoogle Scholar
  20. 20.
    Vandenberghe E, Ruiz de Elvira C, Loberiza FR, Conde E, López-Guillermo A, Gisselbrecht C, et al. Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol. 2003;120:793–800.CrossRefPubMedGoogle Scholar
  21. 21.
    Artz AS, Pollyea DA, Kocherginsky M, Stock W, Rich E, Odenike O, et al. Performance status and co-morbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2006;12:954–64.CrossRefPubMedGoogle Scholar
  22. 22.
    Lefrère F, Delmer A, Suzan F, Levy V, Belanger C, Djabarri M, 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(4):587–93.CrossRefPubMedGoogle Scholar
  23. 23.
    Freedman AS, Neuberg D, Gribben JG, Mauch P, Soiffer RJ, Fisher DC, et al. High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission. J Clin Oncol. 1998;16:13–8.PubMedGoogle Scholar
  24. 24.
    Till BG, Gooley TA, Crawford N, Gopal AK, Maloney DG, Petersdorf SH, et al. Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma. Leuk Lymphoma. 2008;49:1062–73.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Peccatori J, Barkholt L, Demirer T, Sormani MP, Bruzzi P, Ciceri F, on behalf of EBMT, et al. Prognostic factors for survival in patients with advanced renal cell carcinoma undergoing nonmyeloablative allogeneic stem cell transplantation. Cancer. 2005;104(10):2099–103.CrossRefPubMedGoogle Scholar
  26. 26.
    Brunvand MW, Bensinger WI, Soll E, Weaver CH, Rowley SD, Appelbaum FR, et al. High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: Comparison of autologous bone marrow and peripheral blood stem cells. Bone Marrow Transplant. 1996;18(1):131–41.PubMedGoogle Scholar
  27. 27.
    Khouri IF, Lee MS, Romaguera J, Mirza N, Kantarjian H, Korbling M, et al. Allogeneic hematopoietic transplantation for mantle-cell lymphoma:molecular remissions and evidence of graft-versus-malignancy. Ann Oncol. 1999;10:1293–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Berdeja JG, Jones RJ, Zahurak ML, Piantadosi S, Abrams RA, Borowitz MJ, et al. Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma. Biol Blood Marrow Transplant. 2001;7:561–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Rifkind J, Mollee P, Messner HA, Lipton JH. Allogeneic stem cell transplantation for mantle cell lymphoma—does it deserve a better look? Leuk Lymphoma. 2005;46:217–23.CrossRefPubMedGoogle Scholar
  30. 30.
    Ganti AK, Bierman PJ, Lynch JC, Bociek RG, Vose JM, Armitage JO. Hematopoietic stem cell transplantation in mantle cell lymphoma. Ann Oncol. 2005;16:618–24.CrossRefPubMedGoogle Scholar
  31. 31.
    Laudi N, Arora M, Burns L, McGlave P, Miller J, Bohac G, et al. Efficacy of high-dose therapy and hematopoietic stem cell transplantation for mantle cell lymphoma. Am J Hematol. 2006;81:519–24.CrossRefPubMedGoogle Scholar
  32. 32.
    Tsai T, Goodman S, Saez R, Schiller G, Adkins D, Callander N, et al. Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant. 1997;20:859–63.CrossRefPubMedGoogle Scholar
  33. 33.
    Ringden O, Labopin M, Frassoni F, Sanz GF, Demeocq F, Prentice HG, et al. Allogeneic bone marrow transplant or second autograft in patients who relapse after an autograft. Bone Marrow Transplant. 1999;24:389–96.CrossRefPubMedGoogle Scholar
  34. 34.
    Tessoulin B, Ceballos P, Chevaller P, Blaise D, Tournilhac O, Gauthier J, et al. Allogeneic stem cell transplantation for patients with mantle cell lymphoma who failed autologous stem cell transplantation:a national survey of the SFGM-TC. Bone Marrow Transplant. 2016;51(9):1184–90.CrossRefPubMedGoogle Scholar
  35. 35.
    Marks DI, Lush R, Cavenagh J, Milligan DW, Schey S, Parker A, et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood. 2002;100:3108–14.CrossRefPubMedGoogle Scholar
  36. 36.
    Fenske TS, Hamadani M, Cohen JB, Costa LJ, Kahl BS, Evens AM, et al. Allogeneic hematopoietic cell transplantation as curative therapy for patients with non-hodgkin lymphoma: increasingly successful application to older patients. Biol Blood Marrow Transplant. 2016;22(9):1543–51.CrossRefPubMedGoogle Scholar
  37. 37.
    Kruger WH, Hirt C, Basara N, Sayer HG, Behre G, Fischer T, et al. Allogeneic stem cell transplantation for mantle cell lymphoma-final report from the prospective trial of the East German Study Group Haematology/Oncology (OSHO). Ann Hematol. 2014;93:1587–97.CrossRefPubMedGoogle Scholar
  38. 38.
    Bachanova V, Burns L, Wang T, Carreras J, Gale RP, Wiernik PH, et al. Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor. Bone Marrow Tranplant. 2015;50(2):197–203.CrossRefGoogle Scholar
  39. 39.
    Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, et al. Rituximab after lymphoma-directed conditioning and allogeneic stem cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomized, phase II trial. Lancet Oncol. 2014;15(7):757–66.CrossRefPubMedGoogle Scholar
  40. 40.
    Pott C, Hoster E, Delfau-Larue MH, Beldjord K, Bottcher S, Asnafi V, et al. Molecular remission is an independent predictor of clinical outcome with mantle cell lymphoma after combined immunochemotherapy in MCL intergroup study. Blood. 2010;115:3215–23.CrossRefPubMedGoogle Scholar
  41. 41.
    Dreyling M, Thieblemont C, Gallamini A, Arcaini L, Campo E, Hermine O, et al. ESMO consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma. Ann Oncol. 2013;24:857–77.CrossRefPubMedGoogle Scholar
  42. 42.
    Zinzani PL, Vose JM, Czuczman MS, et al: Phase II multicenter study of the safety and efficacy of single-agent lenalidomide in subjects with relapsed/refractory mantle cell lymphoma: Long-term follow-up analysis of the NHL-003 study. 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8–11, 2012 (abstr 2738).Google Scholar
  43. 43.
    Kouroukis CT, Fernandez LA, Crump M, Gascoyne RD, Chua NS, Buckstein R, et al. A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the national canter institute of Canada clinical trials group (IND 172). Leuk Lymphoma. 2011;52(3):394–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, et al. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011;117(11):2442–51.CrossRefPubMedGoogle Scholar
  45. 45.
    Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C, et al. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy refractory mantle cell lymphoma. Haematologica. 2011;96(7):1008–14.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27:3822–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Ansell SM, Tang H, Kurtin PJ, Koenig PA, Inwards DJ, Shah K, et al. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol. 2011;12:361–8.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Qian Z, Zhang L, Cai Z, Sun L, Wang H, Yi Q, et al. Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leuk Res. 2011;35:380–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximabtreated CD20 tumor cells. Clin Cancer Res. 2008;14:4650–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Zhang L, Qian Z, Cai Z, Sun L, Wang H, Bartlett JB, et al. Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. Am J Hematol. 2009;84:553–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011;22:1622–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Goy A, Sinha R, Wiliams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, et al. Single-agent Lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to Bortezomib: Phase II MCL-001 (EMERGE) Study. J Clin Oncol. 2013;31:3688–95.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012;13:716–23.CrossRefPubMedGoogle Scholar
  54. 54.
    Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma. N Eng J Med. 2015;373:1835–44.CrossRefGoogle Scholar
  55. 55.
    Chang BY, Francesco M, Steggerda S, Chang S, Magadala P, Jawed L, et al. Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression. Presented at the American Association for Cancer Research Annual Meeting 2013, Washington, DC, April 6–10, 2013 (Abstract 923).Google Scholar
  56. 56.
    Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88–94.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with Ibrutinib in relapsed or refracotry mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wang ML, Lee H, Chuang H, Wagner-Bartak N, Hagemeister F, Westin J, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-center, open-lable, phase 2 trial. Lancet Oncol. 2016;17(1):48–56.CrossRefPubMedGoogle Scholar
  59. 59.
    Cheah CY, Chihara D, Romaguera JE, Fowler NH, Seymour JF, Hagemeister FB, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann Oncol. 2015;26:1175–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Maddocks K, Cristian B, Jaglowski S, Flynn J, Jones JA, Porcu P, et al. A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood. 2015;125:242–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, 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;23:3383–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Visco C, Finotto S, Zambello R, Paolini R, Menin A, Zanotti R, et al. Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J Clin Oncol. 2013;31:1442–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Ruella M, Kenderian SS, Shestova O, Fraietta JA, Quayyum S, Zhang Q, et al. The addition of the BTK inhibitor Ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. Clin Cancer Res. 2016;22(11):2684–96.CrossRefPubMedGoogle Scholar
  64. 64.
    Cook G, Smith GM, Kirkland K, Lee J, Pearce R, Thomson K, et al. Outcome following reducedintensity allogeneic stem cell transplantation (RIC alloSCT) for relapsed and refractory mantle cell lymphoma (MCL): a study of the British Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2010;16:1419–27.CrossRefPubMedGoogle Scholar
  65. 65.
    Le Gouill S, Kröger N, Dhedin N, Nagler A, Bouabdallah K, Yakoub-Agha I, et al. Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience. Ann Oncol. 2012;23:2695–703.CrossRefPubMedGoogle Scholar
  66. 66.
    Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, et al. Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2013;19:625–31.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol. 2016;34(11):1256–69CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2016

Authors and Affiliations

  • Erden Atilla
    • 1
  • Pinar Ataca Atilla
    • 1
  • Taner Demirer
    • 2
    Email author
  1. 1.Department of HematologyAnkara University Medical SchoolCebeci/AnkaraTurkey
  2. 2.Medicine and Hematology/Oncology, Department of HematologyAnkara University Medical SchoolCebeci/AnkaraTurkey

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