The Challenge of Treating Elderly Patients with Mantle Cell Lymphoma



Treatment of elderly patients with mantle cell lymphoma is considered a major challenge, due to the peculiar chemorefractory features and continuous relapse pattern of this neoplasm. With a median age of 65 years at presentation, more than half of the patients with newly diagnosed mantle cell lymphoma fall into the category ‘elderly’. The most effective treatment for this type of lymphoma consists of high dose cytarabine followed by upfront autologous stem cell transplantation, but such a therapeutic option is not feasible for the higher age category, due to limiting toxicity. Nevertheless, patients obtaining a complete molecular response, independent of age, can enjoy longstanding event-free survival and even improved overall survival. Thus, it is important to obtain a complete response also in the elderly patients: these considerations justify more intensive approaches.

However, it is fundamental to classify these patients in geriatric categories, objectively identifying those able to receive a chemotherapy aiming at long term control of the disease and patients appropriate only for a palliative therapy, primarily mitigating lymphoma symptoms. Therefore, treatment of elderly patient with mantle cell lymphoma should be individualized, and benefits and possible side effects should be carefully balanced.


Mantle cell lymphoma Elderly Tailored treatment Therapeutic algorithm New drugs Clinical trials Prognostic factors Diagnostic procedures 


  1. 1.
    Dreyling M, Hiddemann W. Current treatment standards and emerging strategies in mantle cell lymphoma. Hematology Am Soc Hematol Educ Program. 2009. p.542–51.Google Scholar
  2. 2.
    Cheah CY, George A, Giné E, et al. Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network. Ann Oncol. 2013;24(8):2119–23.PubMedGoogle Scholar
  3. 3.
    Conconi A, Franceschetti S, Lobetti-Bodoni C, et al. Risk factors of central nervous system relapse in mantle cell lymphoma. Leuk Lymphoma. 2013;54(9):1908–14.PubMedGoogle Scholar
  4. 4.
    Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27(8):1209–13. doi: 10.1200/JCO.2008.19.6121.PubMedGoogle Scholar
  5. 5.
    Fernandez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408–18.PubMedGoogle Scholar
  6. 6.
    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(18):4215–23. doi: 10.1182/blood-2011-12-400580.PubMedGoogle Scholar
  7. 7.
    Hiddemann W, Unterhalt M, Herrmann R, et al. 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. 1998;16:1922–30.PubMedGoogle Scholar
  8. 8.
    Gianni AM, Magni M, Martelli M, et al. Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood. 2003;102(2):749–55.PubMedGoogle Scholar
  9. 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(7):2677–84.PubMedGoogle Scholar
  10. 10.
    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(28):7013–23.PubMedGoogle Scholar
  11. 11.
    Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112(7):2687–93. doi: 10.1182/blood-2008-03-147025.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Hermine O, Hoster E, Walewski J, et al. Alternating courses of 3x CHOP and 3x 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. 2012;120:151.Google Scholar
  13. 13.
    Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27(4):511–8. doi: 10.1200/JCO.2008.16.8435.PubMedGoogle Scholar
  14. 14.
    Griffiths R, Mikhael J, Gleeson M, et al. Addition of rituximab to chemotherapy alone as first-line therapy improves overall survival in elderly patients with mantle cell lymphoma. Blood. 2011;118(18):4808–16. doi: 10.1182/blood-2011-04-348367.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2008. p. 233–7.Google Scholar
  16. 16.
    Nickenig C, Dreyling M, Hoster E, et al. Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer. 2006;107(5):1014–22.PubMedGoogle Scholar
  17. 17.
    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(4):2385–7.PubMedGoogle Scholar
  18. 18.
    Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558–65.PubMedGoogle Scholar
  19. 19.
    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(16):3215–23. doi: 10.1182/blood-2009-06-230250.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer. 2007;7(10):750–62.PubMedGoogle Scholar
  21. 21.
    Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117(1):26–38. doi: 10.1182/blood-2010-04-189977.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Navarro A, Royo C, Hernández L, et al. Molecular pathogenesis of mantle cell lymphoma: new perspectives and challenges with clinical implications. Semin Hematol. 2011;48(3):155–65.PubMedGoogle Scholar
  23. 23.
    Royo C, Salaverria I, Hartmann EM, et al. The complex landscape of genetic alterations in mantle cell lymphoma. Semin Cancer Biol. 2011;21(5):322–34.PubMedGoogle Scholar
  24. 24.
    Jares P, Campo E. Advances in the understanding of mantle cell lymphoma. Br J Haematol. 2008;142(2):149–65. doi: 10.1111/j.1365-2141.2008.07124.x.PubMedGoogle Scholar
  25. 25.
    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(2):185–97.PubMedGoogle Scholar
  26. 26.
    Tiemann M, Schrader C, Klapper W, et al. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol. 2005;131(1):29–38.PubMedGoogle Scholar
  27. 27.
    Klapper W, Hoster E, Determann O, et al. Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL Network. J Hematop. 2009;2(2):103–11. doi: 10.1007/s12308-009-0036-x.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Hoster E, Klapper W, Rosenwald A, et al. Cell proliferation (Ki-67) as prognostic marker in mantle cell lymphoma. Blood. 2012;120:2677.Google Scholar
  29. 29.
    de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications–a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2007;25(7):805–12.PubMedGoogle Scholar
  30. 30.
    Kienle D, Katzenberger T, Ott G, et al. Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors. J Clin Oncol. 2007;25(19):2770–7.PubMedGoogle Scholar
  31. 31.
    Hartmann E, Fernàndez V, Moreno V, et al. Five-gene model to predict survival in mantle-cell lymphoma using frozen or formalin-fixed, paraffin-embedded tissue. J Clin Oncol. 2008;26(30):4966–72. doi: 10.1200/JCO.2007.12.0410.PubMedGoogle Scholar
  32. 32.
    Hernández L, Beà S, Pinyol M, et al. CDK4 and MDM2 gene alterations mainly occur in highly proliferative and aggressive mantle cell lymphomas with wild-type INK4a/ARF locus. Cancer Res. 2005;65(6):2199–206.PubMedGoogle Scholar
  33. 33.
    Salaverria I, Zettl A, Beà S, et al. Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature. J Clin Oncol. 2007;25(10):1216–22.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Dreyling M, Thieblemont C, Gallamini A, 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(4):857–77.PubMedGoogle Scholar
  35. 35.
    Orchard J, Garand R, Davis Z, et al. A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. Blood. 2003;101(12):4975–81.PubMedGoogle Scholar
  36. 36.
    Royo C, Navarro A, Clot G, et al. Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia. 2012;26(8):1895–8. doi: 10.1038/leu.2012.72.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Velders GA, Kluin-Nelemans JC, De Boer CJ, et al. Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol. 1996;14(4):1269–74.PubMedGoogle Scholar
  38. 38.
    Argatoff LH, Connors JM, Klasa RJ, et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood. 1997;89(6):2067–78.PubMedGoogle Scholar
  39. 39.
    Møller MB, Pedersen NT, Christensen BE. Mantle cell lymphoma: prognostic capacity of the Follicular Lymphoma International Prognostic Index. Br J Haematol. 2006;133(1):43–9.PubMedGoogle Scholar
  40. 40.
    Geisler CH, Kolstad A, Laurell A, et al. The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood. 2010;115(8):1530–3. doi: 10.1182/blood-2009-08-236570.PubMedGoogle Scholar
  41. 41.
    van de Schans SA, Janssen-Heijnen ML, Nijziel MR, et al. Validation, revision and extension of the Mantle Cell Lymphoma International Prognostic Index in a population-based setting. Haematologica. 2010;95(9):1503–9. doi: 10.3324/haematol.2009.021113.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Chiappella A, Puccini B, Ferrero S, et al. Retrospective analysis of 206 mantle cell lymphoma patients at diagnosis: mantle cell International Prognostic Index (MIPI) Is a good predictor of death event In patients treated either with Rituximab-chemotherapy or Rituximab-high-dose-chemotherapy. Blood. 2010;116:1784.Google Scholar
  43. 43.
    Budde LE, Guthrie KA, Till BG, et al. Mantle cell lymphoma international prognostic index but not pretransplantation induction regimen predicts survival for patients with mantle-cell lymphoma receiving high-dose therapy and autologous stem-cell transplantation. J Clin Oncol. 2011;29(22):3023–9. doi: 10.1200/JCO.2010.33.7055.PubMedCentralPubMedGoogle Scholar
  44. 44.
    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(6):2271–8.PubMedGoogle Scholar
  45. 45.
    van der Velden VH, Cazzaniga G, Schrauder A, et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(4):604–11.PubMedGoogle Scholar
  46. 46.
    Ladetto M, Magni M, Pagliano G, et al. Rituximab induces effective clearance of minimal residual disease in molecular relapses of mantle cell lymphoma. Biol Blood Marrow Transplant. 2006;12:1270–6.PubMedGoogle Scholar
  47. 47.
    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.PubMedGoogle Scholar
  48. 48.
    Ferrero S, Monitillo L, Mantoan B, et al. Pre-emptive rituximab-based treatment of molecular relapses in follicular and mantle cell lymphoma. Ann Hematol. 2013;92(11):1503–11.PubMedGoogle Scholar
  49. 49.
    Schmidt C, Dreyling M. Therapy of mantle cell lymphoma: current standards and future strategies. Hematol Oncol Clin North Am. 2008;22(5):953–63. doi: 10.1016/j.hoc.2008.07.001, ix.PubMedGoogle Scholar
  50. 50.
    Hernandez L, Fest T, Cazorla M, et al. p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. Blood. 1996;87(8):3351–9.PubMedGoogle Scholar
  51. 51.
    Pinyol M, Bea S, Plà L, et al. Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis. Blood. 2007;109(12):5422–9.PubMedGoogle Scholar
  52. 52.
    Zanetto U, Dong H, Huang Y, et al. Mantle cell lymphoma with aberrant expression of CD10. Histopathology. 2008;53(1):20–9. doi: 10.1111/j.1365-2559.2008.03060.x.PubMedGoogle Scholar
  53. 53.
    Palumbo GA, Parrinello N, Fargione G, et al. CD200 expression may help in differential diagnosis between mantle cell lymphoma and B-cell chronic lymphocytic leukemia. Leuk Res. 2009;33(9):1212–6. doi: 10.1016/j.leukres.2009.01.017.PubMedGoogle Scholar
  54. 54.
    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(13):4315–21.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Hartmann EM, Campo E, Wright G, et al. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. Blood. 2010;116(6):953–61. doi: 10.1182/blood-2010-01-263806.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Salaverria I, Royo C, Carvajal-Cuenca A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(−) mantle cell lymphoma. Blood. 2013;121(8):1394–402. doi: 10.1182/blood-2012-08-452284.PubMedCentralPubMedGoogle Scholar
  57. 57.
    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(11):1555–62. doi: 10.3324/haematol.2009.010264.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Dictor M, Ek S, Sundberg M, et al. Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt's lymphoma. Haematologica. 2009;94(11):1563–8. doi: 10.3324/haematol.2009.008474.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86.PubMedGoogle Scholar
  60. 60.
    Brepoels L, Stroobants S, De Wever W, et al. Positron emission tomography in mantle cell lymphoma. Leuk Lymphoma. 2008;49(9):1693–701. doi: 10.1080/10428190802216707.PubMedGoogle Scholar
  61. 61.
    Hosein PJ, Pastorini VH, Paes FM, et al. Utility of positron emission tomography scans in mantle cell lymphoma. Am J Hematol. 2011;86(10):841–5. doi: 10.1002/ajh.22126.PubMedGoogle Scholar
  62. 62.
    Cohen JB, Hall NC, Ruppert AS, et al. Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle cell lymphoma. Bone Marrow Transplant. 2013. doi: 10.1038/bmt.2013.46.PubMedGoogle Scholar
  63. 63.
    Romaguera JE, Medeiros LJ, Hagemeister FB, et al. Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer. 2003;97(3):586–91.PubMedGoogle Scholar
  64. 64.
    Salar A, Juanpere N, Bellosillo B, et al. Gastrointestinal involvement in mantle cell lymphoma: a prospective clinic, endoscopic, and pathologic study. Am J Surg Pathol. 2006;30(10):1274–80.PubMedGoogle Scholar
  65. 65.
    Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114(8):1469–76. doi: 10.1182/blood-2009-02-179739.PubMedGoogle Scholar
  66. 66.
    Bernard M, Tsang RW, Le LW, et al. Limited-stage mantle cell lymphoma: treatment outcomes at the Princess Margaret Hospital. Leuk Lymphoma. 2013;54(2):261–7. doi: 10.3109/10428194.2012.711828.PubMedGoogle Scholar
  67. 67.
    Li ZM, Zucca E, Ghielmini M. Open questions in the management of mantle cell lymphoma. Cancer Treat Rev. 2013. doi: 10.1016/j.ctrv.2012.12.013. pii: S0305-7372(13)00008-X. [Epub ahead of print].Google Scholar
  68. 68.
    Kluin-Nelemans HC, Doorduijn JK. Treatment of elderly patients with mantle cell lymphoma. Semin Hematol. 2011;48(3):208–13. doi: 10.1053/j.seminhematol.2011.03.008.PubMedGoogle Scholar
  69. 69.
    Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist. 2000;5(3):224–37.PubMedGoogle Scholar
  70. 70.
    Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol. 2002;20(2):494–502.PubMedGoogle Scholar
  71. 71.
    Balducci L. New paradigms for treating elderly patients with cancer: the comprehensive geriatric assessment and guidelines for supportive care. J Support Oncol. 2003;1(4 Suppl 2):30–7.PubMedGoogle Scholar
  72. 72.
    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(9):1984–92.PubMedGoogle Scholar
  73. 73.
    Schulz H, Bohlius J, Skoetz N, et al. Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin’s lymphoma. Cochrane Database Syst Rev. 2007;(4):CD003805.Google Scholar
  74. 74.
    Zinzani PL, Magagnoli M, Moretti L, et al. Fludarabine-based chemotherapy in untreated mantle cell lymphomas: an encouraging experience in 29 patients. Haematologica. 1999;84(11):1002–6.PubMedGoogle Scholar
  75. 75.
    Foran JM, Rohatiner AZ, Coiffier B, et al. Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenström’s macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol. 1999;17(2):546–53.PubMedGoogle Scholar
  76. 76.
    Zinzani PL, Magagnoli M, Moretti L, et al. Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma. J Clin Oncol. 2000;18(4):773–9.PubMedGoogle Scholar
  77. 77.
    Hiddemann W, Dreyling M. Mantle cell lymphoma: therapeutic strategies are different from CLL. Curr Treat Options Oncol. 2003;4(3):219–26.PubMedGoogle Scholar
  78. 78.
    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(10):3064–71.PubMedGoogle Scholar
  79. 79.
    Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367(6):520–31. doi: 10.1056/NEJMoa1200920.PubMedGoogle Scholar
  80. 80.
    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(15):3383–9.PubMedGoogle Scholar
  81. 81.
    Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(27):4473–9. doi: 10.1200/JCO.2008.17.0001.PubMedGoogle Scholar
  82. 82.
    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. pii: S0140-6736(12)61763-2.PubMedGoogle Scholar
  83. 83.
    Herold M, Schulze A, Niederwieser D, et al. Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin’s lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO# 19). J Cancer Res Clin Oncol. 2006;132(2):105–12.PubMedGoogle Scholar
  84. 84.
    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(11):1442–9. doi: 10.1200/JCO.2012.45.9842.PubMedGoogle Scholar
  85. 85.
    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(4):667–75.PubMedGoogle Scholar
  86. 86.
    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(4):676–84.PubMedGoogle Scholar
  87. 87.
    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(30):4867–74.PubMedGoogle Scholar
  88. 88.
    Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(30):4952–7. doi: 10.1200/JCO.2007.15.3429.PubMedGoogle Scholar
  89. 89.
    Witzig TE, Vose JM, Zinzani PL, 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(7):1622–7. doi: 10.1093/annonc/mdq626.PubMedGoogle Scholar
  90. 90.
    Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(6):690–7. doi: 10.1200/JCO.2010.31.1142.PubMedGoogle Scholar
  91. 91.
    Houot R, Le Gouill S, Ojeda Uribe M, 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(6):1555–61. doi: 10.1093/annonc/mdr450.PubMedGoogle Scholar
  92. 92.
    Bauwens D, Maerevoet M, Michaux L, et al. Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma. Br J Haematol. 2005;131(3):338–40.PubMedGoogle Scholar
  93. 93.
    Ghielmini M, Schmitz SF, 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(4):705–11.PubMedGoogle Scholar
  94. 94.
    Teodorovic I, Pittaluga S, Kluin-Nelemans JC, et al. 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. 1995;13(11):2819–26.PubMedGoogle Scholar
  95. 95.
    Smith MR, Li H, Gordon L, 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(25):3119–26. doi: 10.1200/JCO.2012.42.2444.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Leitch HA, Gascoyne RD, Chhanabhai M, et al. Limited-stage mantle-cell lymphoma. Ann Oncol. 2003;14(10):1555–61.PubMedGoogle Scholar
  97. 97.
    Tam CS, Bassett R, Ledesma C, et al. Mature results of the M.D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113(18):4144–52. doi: 10.1182/blood-2008-10-184200.PubMedGoogle Scholar
  98. 98.
    Hamadani M, Saber W, Ahn KW, 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(4):625–31. doi: 10.1016/j.bbmt.2013.01.009.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Rodríguez J, Gutierrez A, Palacios A, et al. Rituximab, gemcitabine and oxaliplatin: an effective regimen in patients with refractory and relapsing mantle cell lymphoma. Leuk Lymphoma. 2007;48(11):2172–8.PubMedGoogle Scholar
  100. 100.
    Witzig TE, Geyer SM, Kurtin PJ, et al. Salvage chemotherapy with rituximab DHAP for relapsed non-Hodgkin lymphoma: a phase II trial in the North Central Cancer Treatment Group. Leuk Lymphoma. 2008;49(6):1074–80. doi: 10.1080/10428190801993470.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Ruan J, Martin P, Coleman M, et al. Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma. Cancer. 2010;116(11):2655–64. doi: 10.1002/cncr.25055.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Coleman M, Ruan G, Elstrom RL, et al. Metronomic therapy for refractory/relapsed lymphoma: the PEP-C low-dose oral combination chemotherapy regimen. Hematology. 2012;17 Suppl 1:S90–2. doi: 10.1179/102453312X13336169155970.PubMedGoogle Scholar
  103. 103.
    Baiocchi RA, Alinari L, Lustberg ME, 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.PubMedGoogle Scholar
  104. 104.
    Lamm W, Kaufmann H, Raderer M, 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. doi: 10.3324/haematol.2011.041392.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Weigert O, Weidmann E, Mueck R, et al. A novel regimen combining high dose cytarabine and bortezomib has activity in multiply relapsed and refractory mantle cell lymphoma - long-term results of a multicenter observation study. Leuk Lymphoma. 2009;50(5):716–22. doi: 10.1080/10428190902856790.PubMedGoogle Scholar
  106. 106.
    Gerecitano J, Portlock C, Hamlin P, et al. Phase I trial of weekly and twice-weekly bortezomib with rituximab, cyclophosphamide, and prednisone in relapsed or refractory non-Hodgkin lymphoma. Clin Cancer Res. 2011;17(8):2493–501. doi: 10.1158/1078-0432.CCR-10-1498.PubMedGoogle Scholar
  107. 107.
    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(10):2807–12. doi: 10.1182/blood-2010-11-314708.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Kouroukis CT, Fernandez LA, Crump M, et al. A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the National Cancer Institute of Canada Clinical Trials Group (IND 172). Leuk Lymphoma. 2011;52(3):394–9. doi:10.3109/10428194.2010.546015.PubMedGoogle Scholar
  109. 109.
    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(23):3822–9. doi: 10.1200/JCO.2008.20.7977.PubMedGoogle Scholar
  110. 110.
    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(4):361–8. doi: 10.1016/S1470-2045(11)70062-6.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Hess G, Keller H, Atta J, et al. Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on An Ongoing Phase I/II Trial. Blood (ASH Annual Meeting Abstracts). 2011;118:2697.Google Scholar
  112. 112.
    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(7):1085–91. doi: 10.3324/haematol.2011.053173.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Eve HE, Carey S, Richardson SJ, et al. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol. 2012;159(2):154–63. doi: 10.1111/bjh.12008.PubMedGoogle Scholar
  114. 114.
    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(7):716–23. doi: 10.1016/S1470-2045(12)70200-0.PubMedGoogle Scholar
  115. 115.
    Kaufmann H, Raderer M, Wöhrer S, et al. Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood. 2004;104(8):2269–71.PubMedGoogle Scholar
  116. 116.
    Harel S, Bachy E, Haioun C, et al. Efficacy and safety of thalidomide in mantle cell lymphoma: results of the French ATU Program. Blood. 2010;116:1794.Google Scholar
  117. 117.
    Dreyling M, Kluin-Nelemans HC, Beà S, et al. Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma: report of the 11th annual conference of the European Mantle Cell Lymphoma Network. Leuk Lymphoma. 2013;54(4):699–707. doi: 10.3109/10428194.2012.733882.PubMedGoogle Scholar
  118. 118.
    Wang M, Oki Y, Pro B, et al. Phase II study of yttrium-90-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27(31):5213–8. doi: 10.1200/JCO.2009.21.8545.PubMedGoogle Scholar
  119. 119.
    Beaven AW, Shea TC, Moore DT, et al. A phase I study evaluating ibritumomab tiuxetan (Zevalin®) in combination with bortezomib (Velcade®) in relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2012;53(2):254–8. doi: 10.3109/10428194.2011.608445. Epub 2011 Sep 19.PubMedGoogle Scholar
  120. 120.
    Wang M, Rule SA, Martin P, et al. Interim results of an international, multicenter, Phase 2 study of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. Blood. 2012;120:904.Google Scholar
  121. 121.
    Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a Phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, in patients with relapsed or refractory non-Hodgkin lymphoma. Blood. 2010;116:1777.Google Scholar
  122. 122.
    Cartron G, Thieblemont C, Solal-Celigny P, et al. Promising efficacy with the new anti-CD20 antibody GA101 in heavily pre-treated NHL patients – first results from a Phase II study in patients with relapsed/refractory DLBCL and MCL. Blood. 2010;116:2878.Google Scholar
  123. 123.
    Magni M, Di Nicola M, Carlo-Stella C, et al. Safety, tolerability and activity of Ofatumumab, Bendamustine and Dexamethasone combination as first-line treatment of mantle-cell lymphoma in the elderly: a Multicenter Study. Blood. 2011;118:1647.Google Scholar
  124. 124.
    Vose JM, Loberiza FR, Bociek RG, et al. Phase I/II trial of Ofatumumab/Lenalidamide for patients with relasped/refractory B-cell non-Hodgkin lymphoma: high response rate in indolent lymphoma. Blood. 2012;120:3692.Google Scholar
  125. 125.
    Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321(5891):974–7. doi: 10.1126/science.1158545.PubMedGoogle Scholar
  126. 126.
    Viardot A, Goebeler M, Scheele JS, et al. Treatment of patients with non-Hodgkin lymphoma (NHL) with CD19/CD3 bispecific antibody blinatumomab (MT103): double-step dose increase to continuous infusion of 60 μg/m2/d is tolerable and highly effective. Blood. 2010;116:2880.Google Scholar
  127. 127.
    Palanca-Wessels MC, Flinn IW, Sehn LH, et al. A Phase I study of the anti-CD79b antibody-drug conjugate (ADC) DCDS4501A targeting CD79b in relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Blood. 2012;120:56.Google Scholar
  128. 128.
    Lin TS, Blum KA, Fischer DB, et al. Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders. J Clin Oncol. 2010;28(3):418–23. doi: 10.1200/JCO.2009.24.1570.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Holkova B, Perkins EB, Ramakrishnan V, et al. Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res. 2011;17(10):3388–97. doi: 10.1158/1078-0432.CCR-10-2876.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012;119(20):4597–607. doi: 10.1182/blood-2011-10-388298.PubMedGoogle Scholar
  131. 131.
    Davids MS, Roberts AW, Anderson MA, et al. The BCL-2-specific BH3-Mimetic ABT-199 (GDC-0199) is active and well-tolerated in patients with relapsed non-Hodgkin lymphoma: interim results of a Phase I study. Blood. 2012;120:304.Google Scholar
  132. 132.
    Evens AM, Vose JM, Harb W, et al. A Phase II multicenter study of the histone deacetylase inhibitor (HDACi) abexinostat (PCI-24781) in relapsed/refractory follicular lymphoma (FL) and mantle cell lymphoma (MCL). Blood. 2012;120:55.Google Scholar
  133. 133.
    Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996–5010. doi: 10.1200/JCO.2010.29.2201.PubMedGoogle Scholar
  134. 134.
    Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32. doi: 10.1016/j.ejca.2010.10.013.PubMedGoogle Scholar
  135. 135.
    NCCN guidelines for supportive care:

Copyright information

© Springer-Verlag London 2015

Authors and Affiliations

  1. 1.Division of Hematology, Department of Molecular Biotechnologies and Health SciencesUniversity of TorinoTorinoItaly
  2. 2.Department of Medicine IIIUniversity Hospital Großhadern/LMU MünchenMunichGermany

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