Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Diffuse large B-cell lymphoma—treatment approaches in the molecular era

Nature Reviews Clinical Oncology volume 11, pages 12–23 (2014)Cite this article

Subjects

Key Points

  • Molecular analyses have led to the definition of diffuse large B-cell lymphoma (DLBCL) subtypes, with differential therapeutic responses, and identification of driver mutations that represent the 'Achilles Heel' of these tumours

  • DLBCL can be classified into three different molecular cell-of-origin subtypes: germinal centre B-cell (GCB), activated B-cell (ABC) and primary mediastinal B-cell lymphoma (PMBL)

  • Patients with DLBCL at the highest risk for disease relapse after standard immunochemotherapy are patients with ABC DLBCL and those whose tumours harbour MYC translocations

  • Constitutive activation of the NF-κB pathway is the hallmark of ABC DLBCL; sensitivity to upstream versus downstream inhibition of NF-κB is likely determined by specific mutations found in ABC DLBCL

  • Downstream NF-κB pathway inhibitors include those targeting the ubiquitin-proteasome complex; upstream inhibitors include inhibitors of B-cell receptor signalling and inhibitors targeting other aberrant signalling pathways in ABC DLBCL

  • Overcoming drug resistance in DLBCL will ultimately require identification of cooperating mutations and rational combination therapies targeting the signalling pathways implicated in the pathogenesis of this disease

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin lymphoma that affects patients of all ages with a wide range of clinical presentations. Although DLBCL is curable even in advanced stages, up to one-third of patients will not achieve cure with initial therapy. In the modern era of rituximab-based therapy as the first-line treatment, the prognoses of patients who require salvage therapy are poor and most will eventually succumb to their disease. Insight into the complex molecular circuitry of DLBCL reveals a diverse range of somatic mutations and aberrant intracellular signalling pathways that characterize distinct molecular subsets of the disease. The next major breakthrough in DLBCL therapy during this 'molecular era' of disease definition will be the identification of combinations of novel agents that target the oncogenic drivers of these subsets. Well-conducted clinical trials, with translational molecular investigations, will be essential to achieve the goal of precision medicine and expand the number of patients with DLBCL who achieve a cure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Gene-expression profiling subdivides morphologically indistinguishable DLBCL tumours into three distinct cell-of-origin subtypes.18
Figure 2: The key signalling pathways implicated in GCB DLBCL with targeted novel agents in clinical development.
Figure 3: The key signalling pathways implicated in ABC DLBCL with targeted novel agents in clinical development.
Figure 4: Constitutive activation of the NF-κB pathway is the hallmark of ABC DLBCL and occurs through a variety of mechanisms.82

Similar content being viewed by others

References

  1. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11–30 (2013).

    Article  PubMed  Google Scholar 

  2. Armitage, J. O. My treatment approach to patients with diffuse large B-cell lymphoma. Mayo Clin. Proc. 87, 161–171 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Friedberg, J. W. Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am. Soc. Hematol. Educ. Program 2011, 498–505 (2011).

    Article  PubMed  Google Scholar 

  4. Gisselbrecht, C. et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J. Clin. Oncol. 28, 4184–4190 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  5. DeVita, V. T. Jr et al. Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1, 248–250 (1975).

    Article  PubMed  Google Scholar 

  6. Fisher, R. I. et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N. Engl. J. Med. 328, 1002–1006 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Pfreundschuh, M. et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 7, 379–391 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Coiffier, B. et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116, 2040–2045 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pfreundschuh, M. et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 12, 1013–1022 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Fu, K. et al. Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large b-cell lymphoma. J. Clin. Oncol. 26, 4587–4594 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Schmitz, N. et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002–1). Lancet Oncol. 13, 1250–1259 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Cunningham, D. et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381, 1817–1826 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Récher, C. et al. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03–2B): an open-label randomised phase 3 trial. Lancet 378, 1858–1867 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Wilson, W. H. et al. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97, 758–765 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dunleavy, K. et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N. Engl. J. Med. 368, 1408–1416 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  18. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Rosenwald, A. et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 1937–1947 (2002).

    Article  PubMed  Google Scholar 

  20. Lenz, G. et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc. Natl Acad. Sci. USA 105, 13520–13525 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wright, G. et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 100, 9991–9996 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rosenwald, A. et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J. Exp. Med. 198, 851–862 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Steinhardt, J. J. & Gartenhaus, R. B. Promising personalized therapeutic options for diffuse large B-cell lymphoma subtypes with oncogene addictions. Clin. Cancer Res. 18, 4538–4548 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 43, 830–837 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 110, 1398–1403 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. [No authors listed] A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N. Engl. J. Med. 329, 987–994 (1993).

  29. Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Savage, K. J. et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 114, 3533–3537 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Jaffe, E. S. & Pittaluga, S. Aggressive B-cell lymphomas: a review of new and old entities in the WHO classification. Hematology Am. Soc. Hematol. Educ. Program 2011, 506–514 (2011).

    Article  PubMed  Google Scholar 

  32. Johnson, N. A. et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 114, 2273–2279 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aukema, S. M. et al. Double-hit B-cell lymphomas. Blood 117, 2319–2331 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Snuderl, M. et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am. J. Surg. Pathol. 34, 327–340 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dunleavy, K. et al. MYC+ aggressive B-cell lymphomas: novel therapy of untreated Burkitt lymphoma (BL) and MYC+ diffuse large B-cell lymphoma (DLBCL) with DA-EPOCH-R [abstract]. Ann. Oncol. 22 (Suppl. 4), a071 (2011).

    Google Scholar 

  36. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  37. Cuccuini, W. et al. MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by followed by BEAM plus autologous stem cell transplantation. Blood 119, 4619–4624 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Green, T. M. et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J. Clin. Oncol. 30, 3460–3467 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Johnson, N. A. et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J. Clin. Oncol. 30, 3452–3459 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hu, S. et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 121, 4021–4031 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Horn, H. et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121, 2253–2263 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Thieblemont, C. et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J. Clin. Oncol. 29, 4079–4087 (2011).

    Article  PubMed  Google Scholar 

  43. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kirmizis, A. et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 18, 1592–1605 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yap, D. B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sneeringer, C. J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107, 20980–20985 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Béguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Velichutina, I. et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116, 5247–5255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Qi, W. et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl Acad. Sci. USA 109, 21360–21365 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  52. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  53. Pfeifer, M. et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 110, 12420–12425 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Siebert, R. et al. Deletions in the long arm of chromosome 10 in lymphomas with t(14;18): a pathogenetic role of the tumor supressor genes PTEN/MMAC1 and MXI1? Blood 92, 4487–4489 (1998).

    CAS  PubMed  Google Scholar 

  55. Rodon, J., Dienstmann, R., Serra, V. & Tabernero, J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 10, 143–153 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Lannutti, B. J. 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 117, 591–594 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Furman, R. R. et al. CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia [abstract]. Blood 116, a55 (2010).

    Google Scholar 

  58. Smith, S. M. et al. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: the University of Chicago phase II consortium. J. Clin. Oncol. 28, 4740–4746 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Witzig, T. E. et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 25, 341–347 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Petrich, A. M. et al. Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. Clin. Cancer Res. 18, 2534–2544 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  62. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  63. Iqbal, J. et al. BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. Am. J. Pathol. 165, 159–166 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schuetz, J. M. et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia 26, 1383–1390 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Wilson, W. H. 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. 11, 1149–1159 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Davids, M. S. 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 [abstract]. Blood 120, a304 (2012).

    Article  CAS  Google Scholar 

  68. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  69. Phan, R. T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Basso, K. & Dalla-Favera, R. BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv. Immunol. 105, 193–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Cerchietti, L. C. et al. A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo. Blood 113, 3397–3405 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cerchietti, L. C. et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 17, 400–411 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rawlings, D. J., Schwartz, M. A., Jackson, S. W. & Meyer-Bahlburg, A. Integration of B cell responses through Toll-like receptors and antigen receptors. Nat. Rev. Immunol. 12, 282–294 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lim, K. H., Yang, Y. & Staudt, L. M. Pathogenetic importance and therapeutic implications of NF-κB in lymphoid malignancies. Immunol. Rev. 246, 359–378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Davis, R. E., Brown, K. D., Siebenlist, U. & Staudt, L. M. Constitutive nuclear factor κB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rui, L., Schmitz, R., Ceribelli, M. & Staudt, L. M. Malignant pirates of the immune system. Nat. Immunol. 12, 933–940 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Rawlings, D. J., Sommer, K. & Moreno-García, M. E. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat. Rev. Immunol. 6, 799–812 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ngo, V. N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Kato, M. et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 459, 712–716 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Lam, L. T. et al. Small molecule inhibitors of IκB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin. Cancer Res. 11, 28–40 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Strauss, S. J. et al. The proteasome inhibitor bortezomib acts independently of p53 and induces cell death via apoptosis and mitotic catastrophe in B-cell lymphoma cell lines. Cancer Res. 67, 2783–2790 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Dunleavy, K. et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113, 6069–6076 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ruan, J. et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J. Clin. Oncol. 29, 690–697 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  89. Gu, J. J. et al. The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma. Br. J. Haematol. 162, 657–669 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dasmahapatra, G. et al. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood 115, 4478–4487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dasmahapatra, G. et al. The irreversible proteasome inhibitor carfilzomib interacts synergistically with the selective HDAC6 inhibitor ACY1215 in ABC- and GC-DLBCL and mantle cell lymphoma sensitive or resistant to bortezomib [abstract]. Blood 120, a2765 (2012).

    Google Scholar 

  92. Dasmahapatra, G. et al. Obatoclax interacts synergistically with the irreversible proteasome inhibitor carfilzomib in GC- and ABC-DLBCL cells in vitro and in vivo. Mol. Cancer Ther. 11, 1122–1132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  94. Tageja, N. Lenalidomide - current understanding of mechanistic properties. Anticancer Agents Med. Chem. 11, 315–326 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Yang, Y. et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21, 723–737 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang, L. H. et al. Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br. J. Haematol. 160, 487–502 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Hernandez-Ilizaliturri, F. J. et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 117, 5058–5066 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Dal Porto, J. M. et al. B cell antigen receptor signaling 101. Mol. Immunol. 41, 599–613 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gauld, S. B., Dal Porto, J. M. & Cambier, J. C. B cell antigen receptor signaling: roles in cell development and disease. Science 296, 1641–1642 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Young, R. M. & Staudt, L. M. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat. Rev. Drug Discov. 12, 229–243 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Winer, E. S., Ingham, R. R. & Castillo, J. J. PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies. Expert Opin. Investig. Drugs 21, 355–361 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Honigberg, L. A. 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. USA 107, 13075–13080 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Yang, Y. et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21, 723–737 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Advani, R. H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol. 31, 88–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Wilson, W. H. et al. The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study [abstract]. Blood 120, a686 (2012).

    Google Scholar 

  107. Younes, A. et al. Phase Ib study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL) [abstract]. J. Clin. Oncol. 31, a8502 (2013).

    Google Scholar 

  108. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  109. Saijo, K. et al. Protein kinase C β controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase α. J. Exp. Med. 195, 1647–1652 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kim, S. W. et al. Protein kinase C-associated kinase is required for NF-κB signaling and survival in diffuse large B-cell lymphoma cells. Blood 111, 1644–1653 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase C β inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol. 25, 1741–1746 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Hainsworth, J. D. et al. Randomized phase II study of R-CHOP plus enzastaurin versus R-CHOP in the first line treatment of patients with intermediate and high-risk diffuse large B-cell lymphoma (DLBCL)—preliminary analysis [abstract]. Ann. Oncol. 22 (Suppl. 4), a074 (2011).

    Google Scholar 

  113. Naylor, T. L. et al. Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas. Cancer Res. 71, 2643–2653 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  115. Ferch, U. et al. Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 206, 2313–2320 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hailfinger, S. et al. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 106, 19946–19951 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  117. McAllister-Lucas, L. M., Baens, M. & Lucas, P. C. MALT1 protease: a new therapeutic target in B lymphoma and beyond? Clin. Cancer Res. 17, 6623–6631 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Fontan, L. et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 22, 812–824 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Nagel, D. et al. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 22, 825–837 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Young, R. M. & Staudt, L. M. A new “brew” of MALT1 inhibitors. Cancer Cell 22, 706–707 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lam, L. T. et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma. Blood 111, 3701–3713 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ding, B. B. et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 111, 1515–1523 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Scuto, A. et al. STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma. Cancer Res. 71, 3182–3188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mascarenhas, J. & Hoffman, R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin. Cancer Res. 18, 3008–3014 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  126. Younes, A. et al. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes. J. Clin. Oncol. 30, 4161–4167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Grant, C. et al. Primary mediastinal large B-cell lymphoma, classic Hodgkin lymphoma presenting in the mediastinum, and mediastinal gray zone lymphoma: what is the oncologist to do? Curr. Hematol. Malig. Rep. 6, 157–163 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Savage, K. J. et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102, 3871–3879 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Eberle, F. C. et al. Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma. Haematologica 96, 558–566 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Isaacson, P. G., Norton, A. J. & Addis, B. J. The human thymus contains a novel population of B lymphocytes. Lancet 2, 1488–1491 (1987).

    Article  CAS  PubMed  Google Scholar 

  131. Steidl, C. & Gascoyne, R. D. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood 118, 2659–2669 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Lenz, G. & Staudt, L. M. Aggressive lymphomas. N. Engl. J. Med. 362, 1417–1429 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Feuerhake, F. et al. NFκB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood 106, 1392–1399 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Guiter, C. et al. Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Blood 104, 543–549 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Joos, S. et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87, 1571–1578 (1996).

    CAS  PubMed  Google Scholar 

  136. Green, M. R. et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116, 3268–3277 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Rui, L. et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18, 590–605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chen, B. J. et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 19, 3462–3473 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Steidl, C. et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Berger, R. et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 3044–3051 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Rounbehler, R. J. et al. Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state. Cell 150, 563–574 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lim, K.-H., Romero, D. L., Chaudhary, D., Robinson, S. D. & Staudt, L. M. IRAK4 kinase as a novel therapeutic target in the ABC subtype of diffuse large B cell lymphoma [abstract]. Blood 120, a62 (2012).

    Google Scholar 

  146. Walsh, K. et al. PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin. Cancer Res. 19, 1106–1115 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Han, S. S. et al. NF-κB/STAT3/PI3K signaling crosstalk in iMyc E mu B lymphoma. Mol. Cancer 9, 97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shortt, J. et al. Combined inhibition of PI3K-related DNA-damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas. Blood 121, 2964–2974 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Hernandez-Ilizaliturri, F. J. et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 117, 5058–5066 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge support from the intramural research programme of the NIH.

Author information

Authors and Affiliations

  1. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10 Room 4N115, Bethesda, 20892, MD, USA

    Mark Roschewski, Louis M. Staudt & Wyndham H. Wilson

Authors
  1. Mark Roschewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Louis M. Staudt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wyndham H. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, made a substantial contribution to discussion of the content, wrote the article and reviewed and edited the manuscript prior to submission.

Corresponding author

Correspondence to Wyndham H. Wilson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roschewski, M., Staudt, L. & Wilson, W. Diffuse large B-cell lymphoma—treatment approaches in the molecular era. Nat Rev Clin Oncol 11, 12–23 (2014). https://doi.org/10.1038/nrclinonc.2013.197

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2013.197

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer