Skip to main content

Advertisement

Log in

Novel Agents in Mantle Cell Lymphoma

  • Lymphomas (PA Hamlin, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma, comprising approximately 6–8 % of all non-Hodgkin lymphomas. MCL is biologically and clinically heterogeneous, and there is no standard treatment for MCL. Although untreated MCL often responds well to frontline combination chemotherapy, relapsed, refractory MCL can be challenging to treat and traditional cytotoxic chemotherapy is typically not highly effective. In recent years, increased insight into the molecular and genomic diversity of MCL and the pathogenesis of the disease has given rise to the development of many new biologically targeted therapies. Ibrutinib was recently FDA approved for relapsed, refractory MCL and will likely have a significant impact on treatment paradigms for MCL. In addition to ibrutinib, there are many classes of novel agents that are currently in development. This review focuses on recent developments in the management of relapsed, refractory MCL, describing the growing armamentarium of novel agents available to combat this disease.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 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.

    Article  PubMed  Google Scholar 

  2. Bosch F, Jares P, Campo E, et al. PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma. Blood. 1994;84:2726–32.

    CAS  PubMed  Google Scholar 

  3. Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. 2012;122:3416–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Nordstrom L, Sernbo S, Eden P, et al. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma—a Nordic Lymphoma Group study. Br J Haematol. 2014;166:98–108.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Bernard M, Gressin R, Lefrere F, et al. Blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype. Leukemia. 2001;15:1785–91.

    Article  CAS  PubMed  Google Scholar 

  6. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3:185–97.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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;112:2687–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Schaffel R, Hedvat CV, Teruya-Feldstein J, et al. Prognostic impact of proliferative index determined by quantitative image analysis and the International Prognostic Index in patients with mantle cell lymphoma. Ann Oncol. 2010;21:133–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. 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;131:29–38.

    Article  PubMed  Google Scholar 

  11. Vogt N, Klapper W. Variability in morphology and cell proliferation in sequential biopsies of mantle cell lymphoma at diagnosis and relapse: clinical correlation and insights into disease progression. Histopathology. 2013;62:334–42.

    Article  PubMed  Google Scholar 

  12. Bea S, Valdes-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A. 2013;110:18250–5. This study defines genomic alterations that explain differential sensitivity to ibrutinib in MCL cell lines.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119:1963–71.

    Article  CAS  PubMed  Google Scholar 

  14. Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014;20:87–92.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang J, Jima D, Moffitt AB, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123:2988–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Parekh S, Weniger MA, Wiestner A. New molecular targets in mantle cell lymphoma. Semin Cancer Biol. 2011;21:335–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Perez-Galan P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117:26–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:3383–9. Phase II study showing remarkable efficacy of the BTK-inhibitor ibrutinib and led to breakthrough FDA-approval of ibrutinib in MCL.

    Article  CAS  PubMed  Google Scholar 

  19. O’Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol. 2005;23:676–84.

    Article  PubMed  Google Scholar 

  20. Rodriguez 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;48:2172–8. The phase II study that led to FDA-approval of lenalidomide in patients who previously received bortezomib.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.

    Article  CAS  PubMed  Google Scholar 

  23. 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;119:4597–607.

    Article  CAS  PubMed  Google Scholar 

  24. Dasmahapatra G, Lembersky D, Son MP, et al. Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2011;10:1686–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123:3398–405.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Seymour JF, Gerecitano JF, Kahl BS, et al.: The single-agent Bcl-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in all mantle cell lymphoma (MCL) patients. Presented at the ASH, 2013.

  27. 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;108:4003–8.

    Article  CAS  PubMed  Google Scholar 

  28. 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;49:1074–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. 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;26:4473–9.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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. The phase II study that led to FDA-approval of bortezomib.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. 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;381:1203–10.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  Google Scholar 

  35. 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;20:520–5.

    Article  CAS  PubMed  Google Scholar 

  36. 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;52:394–9.

    Article  CAS  PubMed  Google Scholar 

  37. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Zinzani PL, Vose JM, Czuczman MS, et al. Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Ann Oncol. 2013;24:2892–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31:119–32.

    Article  CAS  PubMed  Google Scholar 

  41. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.

    Article  CAS  PubMed  Google Scholar 

  43. Fenske TS, Zhang MJ, Carreras J, 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.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Mussetti A, Kumar A, Dahi PB, et al.: Lifting the mantle: unveiling new treatment approaches in relapsed or refractory mantle cell lymphoma. Blood Rev, 2014

  45. Smith SM, Pitcher BN, Jung SH, et al.: Unexpected and serious toxicity observed with combined idelalisib, lenalidomide and rituximab in relapsed/refractory b cell lymphomas: alliance A051201 and A051202. Blood (ASH Annual Meeting Abstracts) 124 (21), 2014

  46. 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;113:508–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005;23:5347–56.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. 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;28:418–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Holkova B, Kmieciak M, Perkins EB, et al. Phase I trial of bortezomib (PS-341; NSC 681239) and “nonhybrid” (bolus) infusion schedule of alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms. Clin Cancer Res. 2014;20:5652–62.

    Article  CAS  PubMed  Google Scholar 

  52. Morschhauser F, Bouabdallah K, Stilgenbauer S, et al.: Clinical activity of abemaciclib (LY2835219), a cell cycle inhibitor selective for CDK4 and CDK6, in patients with relapsed or refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts) 124 (21), 2014

  53. Infante JR, Shapiro GI, Witteveen PO, et al.: A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. J Clin Oncol (ASCO Abstract) 32 (5s), 2014

  54. Davids MS, Seymour JF, Gerecitano J, et al.: Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol (ASCO Abstract) 32:5s (suppl), 2014

  55. Evens A, Vose J, 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 (ASH Annual Meeting Abstracts) 120, 2012

  56. Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31:2912–9.

    Article  CAS  PubMed  Google Scholar 

  57. Cheng S, Guo A, Lu P, et al.: Functional characterization of BTK mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia, 2014

  58. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Zhao X, Bodo J, Sun D, et al.: Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways. Br J Haematol. 2014.

  60. Axelrod M, Ou Z, Brett LK, et al. Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia. 2014;28:407–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Dasmahapatra G, Patel H, Dent P, et al. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol. 2013;161:43–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Intlekofer AM, Younes A. Precision therapy for lymphoma—current state and future directions. Nat Rev Clin Oncol. 2014;11:585–96.

    Article  CAS  PubMed  Google Scholar 

  63. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118:4771–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Wang M, Hagemeister F, Westin J, et al.: ibrutinib and rituximab are an efficacious and safe combination in relapsed mantle cell lymphoma: preliminary results from a phase II clinical trial. Blood (ASH Annual Meeting Abstracts) 124, 2014

  65. Kahl BS, Spurgeon SE, Furman RR, et al.: Results of a phase I study of idelalisib, a PI3Kdelta inhibitor, in patients with relapsed or refractory mantle cell lymphoma (MCL). Blood, 2014

Download references

Compliance with Ethics Guidelines

Conflict of Interest

The author declares that she has no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anita Kumar.

Additional information

This article is part of the Topical Collection on Lymphomas

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, A. Novel Agents in Mantle Cell Lymphoma. Curr Oncol Rep 17, 34 (2015). https://doi.org/10.1007/s11912-015-0460-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-015-0460-2

Keywords

Navigation