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Non-chemotherapy Options for Newly Diagnosed Mantle Cell Lymphoma

  • Lymphoma (JL Muñoz, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Mantle cell lymphoma is a rare and incurable non-Hodgkin lymphoma with a heterogenous clinical presentation. Typically, treatment consists of frontline chemoimmunotherapy induction with or without autologous stem cell transplant (ASCT) as consolidation. However, this approach has the propensity to increase short- and long-term toxicities, such as secondary malignancies, without being curative. Genomic profiling of MCL will allow for greater impact of new targeted therapies in the future and may become a helpful tool to guide treatment. Based on the data discussed, use of non-chemotherapy options may become the preferred approach for frontline therapy as opposed to conventional chemotherapy and hematopoietic stem cell transplants.

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References

  1. Zhou Y, Wang H, Fang W, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004. Cancer. 2008;113(4):791–8.

    Article  PubMed  Google Scholar 

  2. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105(11):1684–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Veloza L, Ribera-Cortada I, Campo E, Mantle cell lymphoma pathology update in the, . WHO classification. Ann Lymphoma. 2016;2019:3.

    Google Scholar 

  4. Berard CW, Dorfman RF. Histopathology of malignant lymphomas. Clin Haematol. 1974;3:39–76.

    Article  Google Scholar 

  5. Toksdorf G, Stein H, Lennert K. Morphological and immunological definition of a malignant lymphoma derived from germinal centre cells with cleaved nuclei (centrocytes). Br J Cancer. 1980;41(2):168–82.

    Article  Google Scholar 

  6. Lennert K, Stein H, Kaiserling E. Cytological and functional criteria for the classification of malignant lymphomata. Br J Cancer Suppl. 1975;2:29–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Weisenburger DD, Kim H, Rappaport H. Mantle-Zone Lymphoma: a follicular variant of intermediate lymphocytic lymphoma. Cancer. 1982;49(7):1429–38.

    Article  CAS  PubMed  Google Scholar 

  8. Dreyling M, Hiddemann W; European MCL Network. Current treatment standards and emerging strategies in mantle cell lymphoma. Hematology Am Soc Hematol Educ Program. 2009:542–51.

  9. Chandran R, Gardiner SK, Simon M, Spurgeon SE. Survival trends in mantle cell lymphoma in the United States over 16 years 1992–2007. Leuk Lymphoma. 2012;53(8):1488–93.

    Article  PubMed  Google Scholar 

  10. Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019;94(6):710–25.

    Article  PubMed  Google Scholar 

  11. Hunter T, Pines J. Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell. 1994;79(4):573–82.

    Article  CAS  PubMed  Google Scholar 

  12. Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672–7.

    Article  CAS  PubMed  Google Scholar 

  13. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002;2(2):103–12.

    Article  CAS  PubMed  Google Scholar 

  14. Ek S, Dictor M, Jerkeman M, et al. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008;111(2):800–5.

    Article  CAS  PubMed  Google Scholar 

  15. Wang X, Asplund AC, Porwit A, et al. The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: correlation to overall survival. Br J Haematol. 2008;143:248–52.

    Article  PubMed  Google Scholar 

  16. Nygren L, Baumgartner WS, Klimkowska M, et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood. 2012;119:4215–23.

    Article  CAS  PubMed  Google Scholar 

  17. Fernàndez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70(4):1408–18.

    Article  PubMed  CAS  Google Scholar 

  18. Narurkar R, Alkayem M, Liu D. SOX11 is a biomarker for cyclin D1-negative mantle cell lymphoma. Biomark Res. 2016;4:6.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647–56.

    Article  CAS  PubMed  Google Scholar 

  20. Hoster E, Dreyling M, Klapper W, et al; German Low Grade Lymphoma Study Group (GLSG); European Mantle Cell Lymphoma Network. A new prognostic index (MIPI) for patients with advanced stage mantle cell lymphoma. Blood. 2008;111:558–565.

  21. Chiappella A, Frairia C, Puccini B, et al. Mantle Cell Lymphoma International Prognostic Index (MIPI) and biological-MIPI are better predictors of the outcome of mantle cell lymphoma (MCL) patients than IPI: A retrospective analysis. Haematologica. 2009;94:395.

    Article  CAS  Google Scholar 

  22. Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014;32:1338–46.

    Article  PubMed  Google Scholar 

  23. Geisler CH, Kolstad A, Laurell A, et al; Nordic Lymphoma Group. Nordic MCL2 trial update: six year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012;158:355–362.

  24. Salek D, Vesela P, Boudova L, et al. Retrospective analysis of 235 unselected patients with mantle cell lymphoma confirms prognostic relevance of Mantle Cell Lymphoma International Prognostic Index and Ki-67 in the era of rituximab: long-term data from the Czech Lymphoma Project Database. Leuk Lymphoma. 2014;55:802–10.

    Article  CAS  PubMed  Google Scholar 

  25. Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565–75.

  26. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520–31.

    Article  CAS  PubMed  Google Scholar 

  27. Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34(12):1386–94.

    Article  CAS  PubMed  Google Scholar 

  28. Delfau-Larue MH, Klapper W, Berger F et al; European Mantle Cell Lymphoma Network. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126(5):604–11.

  29. Scott DW, Abrisqueta P, Wright GW, et al. New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies. J Clin Oncol. 2017;35:1668–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Holte H, Beiske K, Boyle M, et al. The MCL35 gene expression proliferation assay predicts high-risk MCL patients in a Norwegian cohort of younger patients given intensive first line therapy. Br J Haematol. 2018;183:225–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rauert-Wunderlich H, Mottok A, Scott DW, et al. Validation of the MCL35 gene expression proliferation assay in randomized trials of the European Mantle Cell Lymphoma Network. Br J Haematol. 2019;184:616–24.

    Article  CAS  PubMed  Google Scholar 

  32. Fakhri B, Kahl B. Current and emerging treatment options for mantle cell lymphoma. Ther Adv Hematol. 2017;8(8):223–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Davies F, Baz R. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 2010;24(Suppl 1):S13–9.

    Article  PubMed  Google Scholar 

  34. Dawar R, Hernandez-Ilizaliturri F. The emerging role of lenalidomide in the management of mantle cell lymphoma (MCL). Best Pract Res Clin Haematol. 2012;25(2):185–90.

    Article  CAS  PubMed  Google Scholar 

  35. Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;111(11):5291–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. List A. Lenalidomide: a transforming therapeutic agent in myelodysplastic syndromes. Clin Lymphoma Myeloma. 2009;9(suppl 3):S302–4.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2008;140:36–45.

    CAS  PubMed  Google Scholar 

  39. Song K, Herzog BH, Sheng M, et al. Lenalidomide inhibits lymphangiogenesis in preclinical models of mantle cell lymphoma. Cancer Res. 2013;73:7254–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Moros A, Bustany S, Cahu J, et al. Antitumoral activity of lenalidomide in in vitro and in vivo models of mantle cell lymphoma involves the destabilization of cyclin D1/p27KIP1 complexes. Clin Cancer Res. 2014;20:393–403.

    Article  CAS  PubMed  Google Scholar 

  41. 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  CAS  PubMed  Google Scholar 

  42. Wiernik P, Lossos I, Tuscano J, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:4952–7.

    Article  PubMed  Google Scholar 

  43. Zinzani P, Vose J, Czuczman M, 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  PubMed Central  Google Scholar 

  44. Eve H, Carey S, Richardson S, 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;159:154–63.

    Article  CAS  PubMed  Google Scholar 

  45. Goy A, Sinha R, Williams M, 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  PubMed Central  Google Scholar 

  46. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, et al. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005;11(16):5984–92.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang L, Qian Z, Cai Z, et al. Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. Am J Hematol. 2009;84:553–9.

    Article  CAS  PubMed  Google Scholar 

  48. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132(19):2016–2025. **This phase II trial explored the combination of R2 in patients with untreated MCL and found excellent response rates that were durable with overall minimal toxicities.

  50. Yamshon S, Martin P, Shah B, et al. Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma (MCL): 7-year analysis from a multi-center phase II study. In: 62nd ASH Annual Meeting and Exposition; 2020 Dec 7; ASH; 2020. Abstract 704. **This abstract provided updated information from the Ruan et al trial exploring R2 in untreated MCL patients. At extended follow-up, 7-year PFS and OS were found to be 60% and 73%, respectively.

  51. Chang BY, Francesco M, Steggerda S, et al. Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression. In: American Association for Cancer Research Annual Meeting; 2013; Washington, DC, April 6–10, 2013.

  52. Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122(14):2412–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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(6):507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240–52.

    Article  CAS  PubMed  Google Scholar 

  55. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659–667. *This phase 2 trial evaluated acalabrutinib among R/R MCL patients and although we cannot compare this to other trials directly, it seemed to have better if not similar activity as ibrutinib but with fewer cardiac toxicities.

  56. Tam C, Grigg A, Opat S, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in patients with relapsed/ refractory B-cell malignancies: initial report of a phase 1 first-in-human trial. Blood. 2015;126(23):832.

    Article  Google Scholar 

  57. Tam C, Wang M, Simpson D, et al. Updated safety and efficacy data in the phase 1 trial of patients with mantle cell lymphoma (Mcl) treated with Bruton Tyrosine Kinase (Btk) inhibitor zanubrutinib (Bgb-3111). Hematol Oncol. 2019;37:245–7.

    Article  Google Scholar 

  58. Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. Blood. 2018;132(1):148.

    Article  Google Scholar 

  59. Song Y, Zhou K, Zou D, et al. Zanubrutinib in patients with relapsed/refractory mantle cell lymphoma. Hematol Oncol. 2019;37(S2):45–6.

    Article  Google Scholar 

  60. Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol. 2016;17(1):48–56.

    Article  CAS  PubMed  Google Scholar 

  61. Wang ML, Jain P, Lee HJ, et al. Frontline treatment with ibrutinib plus rituximab (IR) followed by short course R-Hypercvad/MTX is extremely potent and safe in patients (age ≤ 65 years) with mantle cell lymphoma (MCL) - results of Phase-II Window-1 Clinical Trial. Blood. 2019;134 (supplement_1):3987. **To limit chemotherapy, the Window-1 trial evaluated ibrutinib and rituximab (IR) for induction among untreated MCL patients followed by an abbreviated course of chemotherapy. ORR was found to be 100% after IR alone and after consolidation, which led to high rates of 3-year PFS and OS.

  62. Gurudutta, et al. Structural conservation of residues in BH1 and BH2 domains of Bcl-2 family proteins. FEBS Lett. 2005;579:3503–7.

    Article  CAS  PubMed  Google Scholar 

  63. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.

    Article  CAS  PubMed  Google Scholar 

  64. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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. 2015;168(5):765–8.

    Article  CAS  PubMed  Google Scholar 

  66. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211–1223. *To evaluate for synergistic effects of ibrutinib and venetoclax, this phase 2 trial was performed among R/R MCL patients. Although response rates were promising, several patients developed early resistance to therapy.

  67. Agarwal R, Chan YC, Tam CS, et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat Med. 2019;25(1):119–29.

    Article  CAS  PubMed  Google Scholar 

  68. Tam CS, Ramchandren K, Chen R, et al. Ibrutinib plus venetoclax in patients with relapsed/refractory mantle cell lymphoma: results from the safety run-in period of the Phase 3 Sympatico Study. In: 62nd ASH Annual Meeting and Exposition; 2020 Dec 7; ASH; 2020. Abstract 2938.

  69. Chiron D, Bellanger C, Papin A, et al. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood. 2016;128(24):2808–18.

    Article  CAS  PubMed  Google Scholar 

  70. Le Gouill S, Morschhauser F, Chiron D, et al. Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021; 137 (7): 877–887. **The OASIS trial combined obinutzumab with ibrutinib and venetoclax with the thought that addition of obinutuzumab would overcome resistance mechanisms. In the frontline setting, patients achieved complete response rates early on and were found to attain MRD negativity as well.

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  73. Myung J, Kim KB, Crews CM. The ubiquitin proteasome pathway and proteasome inhibitors. Med Res Rev. 2001;21:245–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4:349–60.

    Article  CAS  PubMed  Google Scholar 

  75. 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 

  76. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659–67.

    Article  CAS  PubMed  Google Scholar 

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  1. Division of Hematology and Medical Oncology, Department of Internal Medicine, Michigan Medicine, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA

    Radhika Takiar MD & Tycel Phillips MD

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Takiar, R., Phillips, T. Non-chemotherapy Options for Newly Diagnosed Mantle Cell Lymphoma. Curr. Treat. Options in Oncol. 22, 98 (2021). https://doi.org/10.1007/s11864-021-00900-w

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