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Current Status of Targeted Therapies for Mantle Cell Lymphoma

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Abstract

Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma (NHL) with treatment outcomes that have historically been poorer than those observed with other NHL subtypes. Patients typically present with dvanced-stage disease and frequent extranodal involvement; the median age at diagnosis is >60 years. Recent improvements in progression-free and overall survival have been observed with more dose-intensive strategies, although at least half of patients diagnosed with MCL are not eligible for such treatment approaches based on age and co-morbidities. In addition, therapy options for relapsed MCL are limited. Only bortezomib is approved for treatment of relapsed MCL in the US. Development of targeted therapy approaches to minimize toxicities while preserving anti-neoplastic properties is of particular importance in MCL. Multiple ongoing studies are attempting to build on the known efficacy of bortezomib by evaluating combination regimens with other targeted agents or cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has known activity in MCL, making this an attractive class of agents for further investigation in combination regimens. Rituximab and other monoclonal antibodies are being evaluated for novel roles in MCL treatment, including as maintenance therapy. Other classes of drugs being investigated in MCL are immunomodulatory agents, inhibitors of the phosphoinositide 3-kinase/Akt and B-cell receptor signalling pathways, and inhibitors of bcl-2 and histone deacetylase. Although many of the agents appear to have modest single-agent activity, the favourable toxicity profile of many agents will make them best suited for incorporation into combination regimens.

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References

  1. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood 2009; 114(8): 1469–76

    Article  PubMed  CAS  Google Scholar 

  2. 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

    Article  PubMed  Google Scholar 

  3. Bosch F, Lopez-Guillermo A, Campo E, et al. Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer 1998; 82(3): 567–75

    Article  PubMed  CAS  Google Scholar 

  4. 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

    Article  PubMed  Google Scholar 

  5. 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(5): 1288–94

    Article  PubMed  CAS  Google Scholar 

  6. 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

    Article  PubMed  CAS  Google Scholar 

  7. Hoster E, Unterhalt M, Wormann B, et al. The addition of rituximab to first-line chemotherapy (R-CHOP) results in superior response rates, time to treatment failure and response duration in patients with advanced stage mantle cell lymphoma: long term results of a randomized GLSG trial [abstract no. 3049]. Blood 2008; 112(11): 1048

    Google Scholar 

  8. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 1998; 16(8): 2780–95

    PubMed  CAS  Google Scholar 

  9. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997; 89(11): 3909–18

    Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol 2009; 27(36): 6101–8

    Article  PubMed  CAS  Google Scholar 

  12. Delarue R, Haioun C, Ribrag V, et al. RCHOP and RDHAP followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): final results of a phase II study from the GELA [abstract no. 581]. Blood 2008; 112(11): 218

    Google Scholar 

  13. 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

    Article  PubMed  CAS  Google Scholar 

  14. 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 mantlecell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 2005; 105(7): 2677–84

    Article  PubMed  CAS  Google Scholar 

  15. Martin P, Chadburn A, Christos P, et al. Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies. Ann Oncol 2008; 19(7): 1327–30

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. Weide R, Pandorf A, Heymanns J, et al. Bend-amustine/Mitoxantrone/Rituximab (BMR): a very effective, well tolerated outpatient chemoimmunotherapy for relapsed and refractory CD20-positive indolent malignancies. Final results of a pilot study. Leuk Lymphoma 2004; 45(12): 2445–9

    Article  CAS  Google Scholar 

  19. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany) [abstract no. 405]. Blood 2009; 114(22): 168–9

    Google Scholar 

  20. Inwards DJ, Fishkin PA, Hillman DW, et al. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer 2008; 113(1): 108–16

    Article  PubMed  CAS  Google Scholar 

  21. Cohen BJ, Moskowitz C, Straus D, et al. Cyclophosphamide/fludarabine (CF) is active in the treatment of mantle cell lymphoma. Leuk Lymphoma 2001; 42(5): 1015–22

    Article  PubMed  CAS  Google Scholar 

  22. Foran JM, Rohatiner AZ, Coiffier B, et al. Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenstrom’s macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 1999; 17(2): 546–53

    PubMed  CAS  Google Scholar 

  23. Robak T, Smolewski P, Cebula B, et al. Rituximab combined with cladribine or with cladribine and cyclo-phosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma. Cancer 2006; 107(7): 1542–50

    Article  PubMed  CAS  Google Scholar 

  24. 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

    Article  PubMed  CAS  Google Scholar 

  25. Ansell SM, Inwards DJ, Rowland Jr KM, et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008; 113(3): 508–14

    Article  PubMed  CAS  Google Scholar 

  26. Witzig TE. Current treatment approaches for mantle-cell lymphoma. J Clin Oncol 2005; 23(26): 6409–14

    Article  PubMed  CAS  Google Scholar 

  27. 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(17): 5165–73

    Article  PubMed  CAS  Google Scholar 

  28. Rizzieri DA, Feldman E, Dipersio JF, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008; 14(9): 2756–62

    Article  PubMed  CAS  Google Scholar 

  29. 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 P1 10d, in patients with relapsed or refractory non-Hodgkin lymphoma [abstract no. 1777]. Blood 2010; 116(21): 741 "

    Google Scholar 

  30. Fowler N, Sharman JP, Smith SM, et al. The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity in patients with relapsed/refractory B-Cell malignancies: results from a phase I study [abstract no. 964]. Blood 2010; 116(21): 425

    Google Scholar 

  31. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115(13): 2578–85

    Article  PubMed  CAS  Google Scholar 

  32. 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(9): 1740–5

    Article  PubMed  CAS  Google Scholar 

  33. Habermann TM, Lossos IS, Justice G, et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 2009; 145(3): 344–9

    Article  PubMed  CAS  Google Scholar 

  34. Czuczman MS, Reeder CB, Polikoff J, et al. International study of lenalidomide in relapsed/refractory aggressive non-Hodgkin’s lymphoma [abstract no. 8509]. J Clin Oncol 2008; 26(15s): 456s

    Google Scholar 

  35. Watanabe T, Kato H, Kobayashi Y, et al. Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Cancer Sci 2010; 101(1): 196–200

    Article  PubMed  CAS  Google Scholar 

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. Hagenbeek A, Fayad L, Delwail V, et al. Evaluation of ofatumumab, a novel human CD20 monoclonal antibody, as single agent therapy in rituximab-refractory follicular lymphoma [abstract no. 935]. Blood 2009; 114(22): 385–6

    Google Scholar 

  38. Coiffier B, Bosly A, Wu KL, et al. Ofatumumab monotherapy for treatment of patients with relapsed/progressive diffuse large B-cell lymphoma: results from a multicenter phase II study [abstract no. 3955]. Blood 2010; 116(21): 1613

    Google Scholar 

  39. Hagenbeek A, Gadeberg O, Johnson P, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008; 111(12): 5486–95

    Article  PubMed  CAS  Google Scholar 

  40. Salles G, Morschhauser F, Lamy T, et al. Phase I study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ non-Hodgkin Lymphoma (NHL) [abstract no. 1704]. Blood 2009; 114(22): 679

    Google Scholar 

  41. Sehn LH, Assouline SE, Stewart DA, et al. A phase I study of GA101 (RO5072759) monotherapy followed by maintenance in patients with multiply relapsed/refractory CD20+ malignant disease [abstract no. 934]. Blood 2009; 114(22): 385

    Google Scholar 

  42. Salles A, Morschhauser F, Thieblemont C, et al. Promising efficacy with the new anti-CD20 antibody GA101 in heavily pre-treated patients: first results from a phase II study in patients with relapsed/refractory indolent NHL (INHL) [abstract no. 0558]. Haematologica 2010; 95 Suppl. 2: 221

    Google Scholar 

  43. Goy A, Ford P, Feldman T, et al. A phase I trial of the pan bcl-2 family inhibitor obatoclax mesylate (GX15-070) in combination with bortezomib in patients with relapsed/refractory mantle cell lymphoma [abstract no. 2569]. Blood 2007; 110(11): 757a

    Google Scholar 

  44. Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 2010; 11(12): 1149–59

    Article  PubMed  CAS  Google Scholar 

  45. 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

    Article  PubMed  Google Scholar 

  46. Kane RC, Dagher R, Farrell A, et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 2007; 13 (18 Pt 1): 5291–4

    Article  PubMed  CAS  Google Scholar 

  47. Friedberg JW, Vose JM, Kelly JL, et al. Bendamustine, bortezomib, and rituximab in patients (pts) with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma (NHL): a multicenter phase II clinical trial [abstract no. 924]. Blood 2009; 114(22): 381

    Google Scholar 

  48. Chang JE, Peterson C, Choi S, et al. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study. Br J Haematol. Epub 2011 Aug 16

  49. Morrison VA, Johnson JL, Jung S, et al. A phase II trial of bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma (MCL) (CALGB 50501): results of a planned interim analysis [abstract no. 8106]. J Clin Oncol 2010; 28(15s): 599s

    Google Scholar 

  50. Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005; 23(3): 630–9

    Article  PubMed  CAS  Google Scholar 

  51. Voorhees PM, Dees EC, O’Neil B, et al. The proteasome as a target for cancer therapy. Clin Cancer Res 2003; 9(17): 6316–25

    PubMed  CAS  Google Scholar 

  52. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004; 4(5): 349–60

    Article  PubMed  CAS  Google Scholar 

  53. Perez-Galan P, Roue G, Villamor N, et al. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 2006; 107(1): 257–64

    Article  PubMed  CAS  Google Scholar 

  54. 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(1): 88–95

    PubMed  CAS  Google Scholar 

  55. Fu L, Lin-Lee YC, Pham LV, et al. Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 2006; 107(11): 4540–8

    Article  PubMed  CAS  Google Scholar 

  56. Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol 2009; 20(3): 520–5

    Article  PubMed  CAS  Google Scholar 

  57. Belch A, Kouroukis CT, Crump M, et al. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol 2007; 18(1): 116–21

    Article  PubMed  CAS  Google Scholar 

  58. 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(5): 431–40

    Article  PubMed  Google Scholar 

  59. Goy A, Bernstein SH, McDonald A, et al. Potential biomarkers of bortezomib activity in mantle cell lymphoma from the phase 2 PINNACLE trial. Leuk Lymphoma 2010; 51(7): 1269–77

    Article  PubMed  CAS  Google Scholar 

  60. Dick LR, Fleming PE. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 2010; 15(5-6): 243–9

    Article  PubMed  CAS  Google Scholar 

  61. Witzig TE, Kaufmann SH. Inhibition of the phosphatidy-linositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 2006; 7(4): 285–94

    Article  PubMed  Google Scholar 

  62. Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006; 6(3): 184–92

    Article  PubMed  CAS  Google Scholar 

  63. LoPiccolo J, Blumenthal GM, Bernstein WB, et al. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 2008; 11(1-2): 32–50

    Article  PubMed  CAS  Google Scholar 

  64. Witzig TE, Gupta M. Signal transduction inhibitor therapy for lymphoma. Hematology Am Soc Hematol Educ Program 2010; 2010: 265–70

    Article  PubMed  Google Scholar 

  65. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4(5): 335–48

    Article  PubMed  CAS  Google Scholar 

  66. Briones J. Emerging therapies for B-cell non-Hodgkin lymphoma. Expert Rev Anticancer Ther 2009; 9(9): 1305–16

    Article  PubMed  Google Scholar 

  67. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356(22): 2271–81

    Article  PubMed  CAS  Google Scholar 

  68. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372(9637): 449–56

    Article  PubMed  CAS  Google Scholar 

  69. 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(23): 5347–56

    Article  PubMed  CAS  Google Scholar 

  70. Reeder C, Gornet M, Habermann T, et al. A phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed, agressive non-Hodgkin lymphoma [abstract no. 121]. Blood 2007; 110(11): 44a

    Google Scholar 

  71. Zhou Y, Jin L, Pittaluga S, et al. PI3K a selective inhibitor induces growth inhibition in mantle cell lymphoma [abstract no. 1812]. Blood 2010; 116(21): 757

    Google Scholar 

  72. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011; 117(2): 591–4

    Article  PubMed  CAS  Google Scholar 

  73. Flinn IW, Schreeder MT, Wagner-Johnston N, et al. A phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase p1 10d, in combination with rituximab and/or bendamustine in patients with relapsed or refractory B-cell malignancies [abstract no. 2832]. Blood 2010; 116(21): 1168

    Google Scholar 

  74. Gururajan M, Jennings CD, Bondada S. Cutting edge: constitutive B cell receptor signaling is critical for basal growth of B lymphoma. J Immunol 2006; 176(10): 5715–9

    PubMed  CAS  Google Scholar 

  75. Pogue SL, Kurosaki T, Bolen J, et al. B cell antigen receptor-induced activation of Akt promotes B cell survival and is dependent on Syk kinase. J Immunol 2000; 165(3): 1300–6

    PubMed  CAS  Google Scholar 

  76. Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 2008; 111(4): 2230–7

    Article  PubMed  CAS  Google Scholar 

  77. 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

    Article  PubMed  CAS  Google Scholar 

  78. Kitada S, Zapata JM, Andreeff M, et al. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 2000; 96(2): 393–7

    PubMed  CAS  Google Scholar 

  79. Byrd JC, Shinn C, Waselenko JK, et al. Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 1998; 92(10): 3804–16

    PubMed  CAS  Google Scholar 

  80. Tay K, Shapiro G, Disinski M, et al. Phase I/II study of a hybrid schedule of flavopiridol in relapsed/refractory mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) [abstract no. 8563]. J Clin Oncol 2009; 27(15s): 449s

    Google Scholar 

  81. Ruan J, Coleman M, Leonard JP. Management of relapsed mantle cell lymphoma: still a treatment challenge. Oncology (Williston Park) 2009; 23(8): 683–90

    Google Scholar 

  82. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4(4): 314–22

    Article  PubMed  CAS  Google Scholar 

  83. 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(8): 2269–71

    Article  PubMed  CAS  Google Scholar 

  84. Harel S, Bachy E, Haioun C, et al. Efficacy and safety of thalidomide in mantle cell lymphoma: results of the French ATU Program [abstract no. 1794]. Blood 2010; 116(21): 749

    Google Scholar 

  85. Dredge K, Marriott JB, Dalgleish AG. Immunological effects of thalidomide and its chemical and functional analogs. Crit Rev Immunol 2002; 22(5-6): 425–37

    Article  PubMed  CAS  Google Scholar 

  86. Dredge K, Marriott JB, Macdonald CD, et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002; 87(10): 1166–72

    Article  PubMed  CAS  Google Scholar 

  87. 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

    Article  PubMed  Google Scholar 

  88. Zaja F, De Luca S, Vitolo U, et al. Salvage treatment with lenalidomide and dexamethasone in patients with relapsed refractory mantle cell lymphoma: clinical results and modifications of angiogenic biomarkers [abstract no. 966]. Blood 2010; 116(21): 425–6s

    Google Scholar 

  89. 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 [abstract no. 8030]. J Clin Oncol 2007; 25(18S): 448s

    Google Scholar 

  90. Ahmadi T, Chong EA, Gordon A, et al. Phase II trial of lenalidomide-dexamethasone-rituximab in relapsed or refractory indolent B-cell or mantle cell lymphomas resistant to rituximab [abstract no. 3962]. Blood 2010; 116(21): 1616

    Google Scholar 

  91. Kawamata N, Chen J, Koeffler HP. Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood 2007; 110(7): 2667–73

    Article  PubMed  CAS  Google Scholar 

  92. Kelly WK, O’Connor OA, Marks PA. Histone deacetylase inhibitors: from target to clinical trials. Expert Opin Investig Drugs 2002; 11(12): 1695–713

    Article  PubMed  CAS  Google Scholar 

  93. Leshchenko VV, Kuo PY, Shaknovich R, et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 2010; 116(7): 1025–34

    Article  PubMed  CAS  Google Scholar 

  94. 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(1): 42–50

    Article  PubMed  CAS  Google Scholar 

  95. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007; 109(1): 31–9

    Article  PubMed  CAS  Google Scholar 

  96. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007; 25(21): 3109–15

    Article  PubMed  CAS  Google Scholar 

  97. Kirschbaumm M, Popplewellm L, Delioukinam ML, et al. A phase 2 study of vorinostat (suberoylanilide hydroxamic acid, SAHA) plus rituximab in newly diagnosed, relapsed or refractory indolent non-Hodgkin’s lymphoma [abstract no. 3957]. Blood 2010; 116(21): 1614

    Google Scholar 

  98. Kirschbaum M, Popplewell L, Nademanee A, et al. A phase 2 study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in relapsed or refractory indolent non-Hodgkin’s lymphoma. A California Cancer Consortium study [abstract no. 1564]. Blood 2008; 112(11): 554–5

    Google Scholar 

  99. Rao R, Fiskus W, Yang Y, et al. Co-treatment with panobinostat enhances bortezomib-induced unfolded protein response, endoplasmic reticulum stress and apoptosis of human mantle cell lymphoma cells [abstract no. 887]. Blood 2008; 112(11): 327

    Google Scholar 

  100. Hernandez-Ilizaliturri FJ, Mavis C, Maraj I, et al. Pano-binostat, a novel histone deacetylase (HiDAC) inhibitor enhances the anti-tumor activity of bortezomib (BTZ) in rituximab-chemotherapy sensitive and resistant lymphoma cell lines [abstract no. 3936]. Blood 2010; 116(21): 1605s

    Google Scholar 

  101. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009; 27(10): 1607–14

    Article  PubMed  CAS  Google Scholar 

  102. 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 2011; 377(9759): 42–51

    Article  PubMed  CAS  Google Scholar 

  103. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006; 108(13): 4003–8

    Article  PubMed  CAS  Google Scholar 

  104. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108(10): 3295–301

    Article  PubMed  CAS  Google Scholar 

  105. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010; 28(17): 2853–8

    Article  PubMed  CAS  Google Scholar 

  106. Taverna CJ, Bassi S, Hitz F, et al. First results of long-term rituximab maintenance treatment in follicular lymphoma: Safety analysis of the randomized phase III trial SAKK 35/03 [abstract no. 8534]. J Clin Oncol 2009; 27(15s): 442s

    Google Scholar 

  107. Zucca E, Roggero E, Pinotti G, et al. Patterns of survival in mantle cell lymphoma. Ann Oncol 1995; 6(3): 257–62

    PubMed  CAS  Google Scholar 

  108. 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

    Article  PubMed  CAS  Google Scholar 

  109. Kluin-Nelemans JC, Hoster E, Hermine O, et al. R-CHOP versus R-FC followed by maintenance with rituximab or IFN: first results of a randomized trial for elderly patients with mantle cell lymphoma [abstract no. 016]. Ann Oncol 2011; 22 Suppl. 4: 86

    Article  Google Scholar 

  110. Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood 2003; 101(2): 391–8

    Article  PubMed  CAS  Google Scholar 

  111. Weigert O, von Schilling C, Rummel MJ, et al. Efficacy and safety of a single-course of yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin®) in patients with relapsed or refractory mantle cell lymphoma (MCL) after/not appropriate for autologous stem cell transplantation (ASCT): a phase II trial of the European MCL network [abstract no. 4786]. Blood 2005; 106(11): 277b

    Google Scholar 

  112. Wang M, Oki Y, Pro B, et al. Phase II study of yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) in patients with relapsed and refractory mantle cell lymphoma (MCL) [abstract no. 2714]. Blood 2006; 108(11): 767a

    Google Scholar 

  113. Morschhauser F, Dreyling M, Rohatiner A, et al. Rationale for consolidation to improve progression-free survival in patients with non-Hodgkin ’s lymphoma: a review of the evidence. Oncologist 2009; 14 Suppl. 2: 17–29

    Article  PubMed  CAS  Google Scholar 

  114. Zelenetz AD, Noy A, Pandit-Taskar N, et al. Sequential radioimmunotherapy with tositumomab/iodine I131 to msitumomab followed by CHOP for mantle cell lymphoma demonstrates RIT can induce molecular remissions [abstract no. 7560]. J Clin Oncol 2006; 24(18s): 436a

    Google Scholar 

  115. Smith MR, Zhang L, Gordon LI, et al. Phase II study of R-CHOP followed by 90Y-Ibritumomab tiuxetan in untreated mantle cell lymphoma: Eastern Cooperative Oncology Group Study E1499 [abstract no. 389]. Blood 2007; 110(11): 121a

    Google Scholar 

  116. Jurczak W, Giza A, Krochmalczyk D, et al. Radioimmunotherapy (RIT) as an alternative consolidation of MCL patients not eligible for transplant protocols: final analysis of multicenter Polish Lymphoma Research Group (PLRG) trial with 90Y-Zevalin (90Y-ibritumomab tiuxetan) [abstract no. 303]. Ann Oncol 2008; 19 Suppl. 4: iv173

    Google Scholar 

  117. Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006; 177(1): 362–71

    PubMed  CAS  Google Scholar 

  118. Li B, Zhao L, Guo H,et al. Characterization of a rituximab variant with potent antitumor activity against rituximab-resistant B-cell lymphoma. Blood 2009; 114(24): 5007–15

    Article  PubMed  CAS  Google Scholar 

  119. Du J, Yang H, Guo, et al. Structure of the Fab fragment of therapeutic antibody Ofatumumab provides insights into the recognition mechanism with CD20. Mol Immunol 2009; 46(11-12): 2419–23

    Article  PubMed  CAS  Google Scholar 

  120. Cheson BD. Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J Clin Oncol 2010; 28(21): 3525–30

    Article  PubMed  CAS  Google Scholar 

  121. Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood 2008; 111(3): 1094–100

    Article  PubMed  CAS  Google Scholar 

  122. Wierda WG, Kipps T, Mayer J, et al. Activity of ofatumumab, a novel CD20 mAb, and prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulky fludarabine-refractory chronic lymphocytic leukemia (CLL) [abstract no. 7044]. J Clin Oncol 2009; 27(15s): 366s

    Google Scholar 

  123. Dalle S, Reslan L, Manquat SB, et al. Compared antitumor activity of GA101 and rituximab against the human RL follicular lymphoma xenografts in SCID beige mice [abstract no. 1585]. Blood 2008; 112(11): 562

    Google Scholar 

  124. Herter S, Waldhauer I, Otz T, et al. Superior efficacy of the novel type II, glycoengineered CD20 antibody GA101 vs. the type I CD20 antibodies rituximab and ofatumumab [abstract no. 3925]. Blood 2010; 116(21): 1601

    Google Scholar 

  125. Wright JJ. Combination therapy of bortezomib with novel targeted agents: an emerging treatment strategy. Clin Cancer Res 2010; 16(16): 4094–104

    Article  PubMed  CAS  Google Scholar 

  126. Konopleva M, Watt J, Contractor R, et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 2008; 68(9): 3413–20

    Article  PubMed  CAS  Google Scholar 

  127. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009; 15(4): 1126–32

    Article  PubMed  CAS  Google Scholar 

  128. Nguyen M, Marcellus RC, Roulston A, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A 2007; 104(49): 19512–7

    Article  PubMed  CAS  Google Scholar 

  129. Perez-Galan P, Roue G, Villamor N, et al. The BH3-mi-metic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 2007; 109(10): 4441–9

    Article  PubMed  CAS  Google Scholar 

  130. Perez-Galan P, Roue G, Lopez-Guerra M, et al. BCL-2 phosphorylation modulates sensitivity to the BH3 mimeti GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia 2008; 22(9): 1712–20

    Article  PubMed  CAS  Google Scholar 

  131. Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol 2011; 80(11): 69–86

    Article  PubMed  Google Scholar 

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Acknowledgements

No sources of funding were used in the preparation of this manuscript. Julie Chang has no conflicts of interest that are directly relevant to the content of this review. Brad Kahl has received research funding and consulting fees from Millennium and Genentech.

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  1. Department of Medicine, University of Wisconsin School of Medicine and Public Health and the UW Carbone Cancer Center, 1111 Highland Ave., 4007 Wisconsin Institute for Medical Research, Madison, WI, 53705, USA

    Julie E. Chang MD & Brad S. Kahl

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Correspondence to Julie E. Chang MD.

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Chang, J.E., Kahl, B.S. Current Status of Targeted Therapies for Mantle Cell Lymphoma. Drugs 71, 2307–2326 (2011). https://doi.org/10.2165/11594630-000000000-00000

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