Abstract
Mantle cell lymphoma is a distinct subtype of B-cell non-Hodgkin lymphoma, accounting for 3–10 % of all non-Hodgkin lymphoma cases. The median age at diagnosis is nearly 70 years. The prognosis of patients is based on the Mantle Cell Lymphoma International Prognostic Index, which is calculated on the basis of four independent prognostic factors (age, performance status, serum lactate dehydrogenase and leukocyte count). Treatment of elderly patients with de novo untreated mantle cell lymphoma is based on rituximab combined with chemotherapy. The most commonly used regimen is the classical CHOP21 (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. Bendamustine is also an option, especially for patients with cardiac comorbidities. In elderly patients who are relatively young and fit, an approach based on treatment usually used for younger patients, with cytarabine-based induction followed by autologous stem cell transplantation, should be discussed. Treatment of relapsing patients is based on the use of newer effective drugs, including bortezomib, lenalidomide and thalidomide, and mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus. These drugs are often combined with rituximab and can be prescribed in combination with chemotherapy. Promising new drugs are Bruton tyrosine kinase inhibitors and other inhibitors of the phosphoinositide 3-kinase (PI3K)–mTOR–protein kinase B (AKT) pathway. Despite these new advances, mantle cell lymphoma remains an incurable disease, and further basic and clinical research is warranted.
Similar content being viewed by others
References
Smedby KE, Hjalgrim H. Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Semin Cancer Biol. 2011;21:293–8.
Swerdlow AJ, Campo E, Harris ES, et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon: France IARC Press; 2008.
Wlodarska I, Dierickx D, Vanhentenrijk V, et al. Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas. Blood. 2008;111:5683–90.
Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009;94:1555–62.
Thieblemont C, Rolland D, Baseggio L, et al. Comprehensive analysis of GST-π expression in B-cell lymphomas: correlation with histological subtypes and survival. Leuk Lymphoma. 2008;49:1403–6.
Fu K, Weisenburger DD, Greiner TC, et al. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood. 2005;106:4315–21.
Vose JM. Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2012;87:604–9.
Swerdlow SH, Habeshaw JA, Murray LJ, et al. Centrocytic lymphoma: a distinct clinicopathologic and immunologic entity. A multiparameter study of 18 cases at diagnosis and relapse. Am J Pathol. 1983;113:181–97.
Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111:558–65.
Determann O, Hoster E, Ott G, et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008;111:2385–7.
Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511–8.
Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010;115:3215–23.
Bodet-Milin C, Touzeau C, Leux C, et al. Prognostic impact of 18F-fluoro-deoxyglucose positron emission tomography in untreated mantle cell lymphoma: a retrospective study from the GOELAMS Group. Eur J Nucl Med Mol Imaging. 2010;37:1633–42.
Martin P, Leonard J. Is there a role for “watch and wait” in patients with mantle cell lymphoma? Semin Hematol. 2011;48:189–93.
Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res. 2012;72:5307–16.
Nygren L, Baumgartner Wennerholm S, Klimkowska M, et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood. 2012;119:4215–23.
Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27:1209–13.
Ghielmini M, Schmitz SFH, Cogliatti S, et al. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005;23:705–11.
Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984–92.
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;104:3064–71.
Schulz H, Bohlius JF, Trelle S, et al. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2007;99:706–14.
Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520–31.
Rummel MJ, Niederle N, Maschmeyer G, et al. 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. doi:10.1016/S0140-6736(12)61763-2.
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;16:587–93.
Romaguera JE, Khouri IF, Kantarjian HM, et al. Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma. 2000;39:77–85.
Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood. 2013;121:48–53.
Hermine O, Hoster E, Walewski J, et al. Alternating courses of 3× CHOP and 3× DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: final analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net). Blood (ASH Annual Meeting Abstracts). 2012;120:151.
Visco C, Finotto S, Zambello 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.
Dreyling M, Lenz G, Hoster E, 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.
Jantunen E, Canals C, Attal M, et al. Autologous stem-cell transplantation in patients with mantle cell lymphoma beyond 65 years of age: a study from the European Group for Blood and Marrow Transplantation (EBMT). Ann Oncol. 2012;23:166–71.
Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2010;377:42–51.
Smith MR, Li H, Gordon L, Gascoyne RD, et al. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90–ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012;30:3119–26.
Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol. 2009;27:4365–70.
Kluin-Nelemans HC, Doorduijn JK. Treatment of elderly patients with mantle cell lymphoma. Semin Hematol. 2011;48:208–13.
Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4:349–60.
Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24:4867–74.
Houot R, Gouill SL, Uribe MO, et al. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS. Ann Oncol. 2012;23:1555–61.
Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011;117:2807–12.
Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431–40.
Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol. 2006;7:285–94.
Hess G, Herbrecht R, Romaguera J, 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.
Ansell SM, Tang H, Kurtin PJ, et al. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol. 2011;12:361–8.
Renner C, Zinzani PL, Gressin R, et al. A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica. 2012;97:1085–91.
Castillo JJ, Furman M, Winer ES. CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies. Expert Opin Investig Drugs. 2012;21:15–22.
Khan WN. Regulation of B lymphocyte development and activation by Bruton’s tyrosine kinase. Immunol Res. 2001;23:147–56.
Wang M, Rule SA, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.
Dawar R, Hernandez-Ilizaliturri F. The emerging role of lenalidomide in the management of mantle cell lymphoma (MCL). Best Pract Res Clin Haematol. 2012;25:185–90.
Damaj G, Lefrere F, Delarue R, et al. Thalidomide therapy induces response in relapsed mantle cell lymphoma. Leukemia. 2003;17:1914–5.
Kaufmann H, Raderer M, Wohrer S, et al. Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood. 2004;104:2269–71.
Goy A, Sinha R, Williams ME, 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.
Wang M, Fayad L, Wagner-Bartak N, 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.
Hamaker ME, Jonker JM, De Rooij SE, et al. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol. 2012;13:e437–44.
Funding and Conflict of Interest Disclosure Statements
There was no funding for the preparation of this manuscript. Marguerite Vignon and Marie-Dominique Venon have no conflicts of interest to declare. Olivier Hermine has received consulting fees or honoraria from Celgene, Johnson & Johnson, Roche and Pfizer; support for travel to meetings for the study, manuscript preparation or other purposes from Celgene and Roche; and payment for lectures, including service on speakers’ bureaus from Johnson & Johnson. Richard Delarue has received payment for lectures from Sandoz, Roche, Pfizer and Celgene. He served as a member of a data and safety monitoring board of a study sponsored by Millenium. He has also received travel support from Celgene, Novartis, Roche and Mundipharma.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Vignon, M., Venon, MD., Hermine, O. et al. Management of Mantle Cell Lymphoma in the Elderly: Current and Potential Strategies. Drugs Aging 30, 979–986 (2013). https://doi.org/10.1007/s40266-013-0129-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40266-013-0129-1