Skip to main content
SpringerLink
Log in

Targeted Therapeutics for Lymphoma: Using Biology to Inform Treatment

  • Chapter
  • First Online:
Aggressive Lymphomas

Part of the book series: Hematologic Malignancies ((HEMATOLOGIC))

Abstract

A significant proportion of patients with B- and T-cell aggressive non-Hodgkin lymphomas are not cured by standard of care immunochemotherapy, and recent randomised studies have failed to improve outcomes for patients with the most common type, diffuse large B-cell lymphoma. Advances in molecular biology have confirmed aggressive lymphomas to be molecularly heterogeneous, but at present biological knowledge provides limited guidance for clinical practice. This is likely to change as discovery science and targeted therapies in clinical trials begin to identify subtypes that may respond differentially to specific treatments. This chapter reviews the evidence to date and the prospects for changes to clinical practice in the future.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. SEER. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. SEER 2017. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed 2 Apr 2017.

  2. https://www.hmrn.org/statistics/incidence. Accessed 25 Jun 2017.

  3. Feugier P, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117.

    Article  CAS  PubMed  Google Scholar 

  4. Wilson WH, et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. Blood. 2016;128:469.

    Google Scholar 

  5. d’Amore F, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093–9.

    Article  CAS  PubMed  Google Scholar 

  6. Laport GG. Peripheral T-cell lymphoma: autologous hematopoietic cell transplantation as first-line therapy. Curr Opin Oncol. 2010;22(5):409–13.

    Article  PubMed  Google Scholar 

  7. Mounier N, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003;101:4279.

    Article  CAS  PubMed  Google Scholar 

  8. 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. 2013;381(9880):1817–26.

    Article  CAS  PubMed  Google Scholar 

  9. 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. 2011;378(9806):1858–67.

    Article  PubMed  CAS  Google Scholar 

  10. Jaeger U, et al. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015;2015:125344.

    Google Scholar 

  11. Leppä S, et al. A phase III study of enzastaurin in patients with high-risk diffuse large B cell lymphoma following response to primary treatment: the prelude trial. Am Soc Hematol. 2013.

    Google Scholar 

  12. Witzig TE, et al. PILLAR-2: a randomized, double-blind, placebo-controlled, phase III study of adjuvant everolimus (EVE) in patients (pts) with poor-risk diffuse large B-cell lymphoma (DLBCL). Proc Am Soc Clin Oncol. 2016.

    Google Scholar 

  13. Vitolo U, et al. Obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma: final results from an open-label, randomized phase 3 study (GOYA). Blood. 2016;128:470.

    Article  CAS  Google Scholar 

  14. Thieblemont C, et al. First analysis of an international double-blind randomized phase III study of lenalidomide maintenance in elderly patients with DLBCL treated with R-CHOP in first line, the REMARC study from Lysa. Blood. 2016;128:471.

    Google Scholar 

  15. Davies A, et al. Differential efficacy of bortezomib in subtypes of diffuse large B-cell lymphoma (DLBL): a prospective randomised study stratified by transcriptome profiling: REMODL-B. Hematol Oncol. 2017;35(S2):130–1.

    Article  Google Scholar 

  16. Flinn IW, et al. A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Eur J Cancer. 2016;54:11–7.

    Article  CAS  PubMed  Google Scholar 

  17. Wilson WH, 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. Blood. 2012;120(21):686.

    Google Scholar 

  18. Davids MS, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;70:4320.

    Google Scholar 

  19. Bohl SR, et al. Nivolumab induces remission in high-PD-L1 expressing aggressive B-non Hodgkin lymphoma: a single center experience. Blood. 2016;128:1865.

    Google Scholar 

  20. Oki Y, et al. Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma. Br J Haematol. 2015;171(4):463–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Horwitz SM, et al. Duvelisib (IPI-145), a phosphoinositide-3-kinase-δ, γ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Blood. 2014;124:803.

    Article  CAS  Google Scholar 

  22. Witzig TE, et al. A comprehensive review of lenalidomide therapy for B- cell non-Hodgkin lymphoma. Ann Oncol. 2015;26:1667.

    Article  CAS  PubMed  Google Scholar 

  23. Witzig TE, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia. 2011;25(2):341–7.

    Article  CAS  PubMed  Google Scholar 

  24. Caimi P, et al. A phase 1 study of BET inhibition using RG6146 in relapsed/refractory (R/R) MYC-expressing diffuse large B cell lymphoma (DLBCL). Hematol Oncol. 2017;35(S2):263–5.

    Article  Google Scholar 

  25. Morschhauser F, et al. Interim report from a phase 2 multicenter study of TAZEMETOSTAT, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Hematol Oncol. 2017;35:24–5.

    Article  Google Scholar 

  26. Coiffier B, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7(1):11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Swerdlow SH, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Clozel T, et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 2013;3:1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Morin RD, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole- genome sequencing. Blood. 2013;122:1256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Park HY, et al. Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma. Oncotarget. 2016;7(52):86433.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bertier G, Hétu M, Joly Y. Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views. BMC Med Genet. 2016;9(1):52.

    Google Scholar 

  32. Dubois S, et al. Next generation sequencing in diffuse large B cell lymphoma highlights molecular divergence and therapeutic opportunities: a LYSA study. Clin Cancer Res. 2016;22(12):2919–28.

    Article  CAS  PubMed  Google Scholar 

  33. Davies AJ, et al. Differential efficacy of bortezomib in subtypes of diffuse large B-cell lymphoma (dlbl): a prospective randomised study stratified by transcriptome profiling: remodl-B. Hematol Oncol. 2017;35:130–1.

    Article  Google Scholar 

  34. Scott DW, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123(8):1214–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alizadeh AA, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503.

    Article  CAS  PubMed  Google Scholar 

  36. Monti S, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2005;105(5):1851–61.

    Article  CAS  PubMed  Google Scholar 

  37. Moffitt AB, Dave SS. Clinical applications of the genomic landscape of aggressive non-Hodgkin lymphoma. J Clin Oncol. 2017;35(9):955–62.

    Article  CAS  PubMed  Google Scholar 

  38. Iqbal J, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):2915–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huang Y, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010;115(6):1226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Manso R, et al. C-MYC is related to GATA3 expression and associated with poor prognosis in nodal peripheral T-cell lymphomas. Haematologica. 2016;101(8):e336.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ennishi D, et al. Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell of origin-specific clinical impact. Blood. 2017;129(20):2760–70.

    Article  CAS  PubMed  Google Scholar 

  42. Barrans S, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360–5.

    Article  CAS  PubMed  Google Scholar 

  43. Zhang HW, et al. Clinical impact of t (14; 18) in diffuse large B-cell lymphoma. Chin J Cancer Res. 2011;23(2):160–4.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Oki Y, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891–901.

    Article  CAS  PubMed  Google Scholar 

  45. Dunleavy K, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. Blood. 2014;124(21):395.

    Google Scholar 

  46. Sehn L, et al. Prognostic impact of BCL2 and MYC expression and translocation in untreated DLBCL: results from the phase III GOYA study. Hematol Oncol. 2017;35(S2):131–3.

    Article  Google Scholar 

  47. Lai C, et al. MYC gene rearrangement in diffuse large B-cell lymphoma does not confer a worse prognosis following dose-adjusted EPOCH-R. Leuk Lymphoma. 2018;59:505–8.

    Article  CAS  PubMed  Google Scholar 

  48. Kühnl A, et al. Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: subgroup analysis from the UK NCRI R-CHOP 14 vs 21 trial. Blood. 2015;126:1516.

    Article  CAS  Google Scholar 

  49. Roschewski M, et al. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat Rev Clin Oncol. 2014;11:12–23.

    Article  CAS  PubMed  Google Scholar 

  50. Staiger AM, et al. Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German High-Grade Non-Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2017;35(22):2515–26.

    Article  CAS  PubMed  Google Scholar 

  51. Mareschal S, et al. The proportion of activated B-cell like subtype among de novo diffuse large B-cell lymphoma increases with age. Haematologica. 2011;96(12):1888–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Molina TJ, et al. Young patients with non–germinal center B-cell–like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d’Etudes des Lymphomes de l’Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014;32(35):3996–4003.

    Article  CAS  PubMed  Google Scholar 

  53. Davis RE, et al. Constitutive nuclear factor κB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gang AO, et al. Cell of origin predicts outcome to treatment with etoposide-containing chemotherapy in young patients with high-risk diffuse large B-cell lymphoma. Leuk Lymphoma. 2015;56(7):2039–46.

    Article  CAS  PubMed  Google Scholar 

  55. Byrd JC, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wilson WH, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Young RM, et al. CRISPR-CAS9 genetic screens uncover a B cell receptor-MYD88 superpathway in diffuse large B cell lymphoma. Hematol Oncol. 2017;35:25.

    Article  Google Scholar 

  58. Phelan JD, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature. 2018;560(7718):387–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hernandez-Ilizaliturri FJ, 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. 2011;117(22):5058–66.

    Article  CAS  PubMed  Google Scholar 

  60. Davies A, Caddy J, Maishman T, Barrans S, Mamot C, Care M, Pocock C, Stantion L, Hamid D, Pugh K, Mcmillan A, Fields P, Kruger A, Jack A, Johnson P. A prospective randomised trial of targeted therapy for diffuse large B-cell lymphoma (DLBCL) based upon real-time gene expression profiling: the Remodl-B Study of the UK NCRI and SAKK Lymphoma Groups (ISRCTN51837425). ASH Annual Meeting Abstracts. 2015.

    Google Scholar 

  61. Thieblemont CC, et al. First analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide maintenance in elderly patients with DLBCL treated with R-CHOP in first line, the Remarc Study from Lysa. American Society of Hematology, San Diego, CA. 2016.

    Google Scholar 

  62. Thieblemont C, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017;35(22):2473–81.

    Article  CAS  PubMed  Google Scholar 

  63. Young RM, et al. B-cell receptor signaling in diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):77–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Golay J, et al. Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood. 2013;122(20):3482–91.

    Article  CAS  PubMed  Google Scholar 

  65. Chen L, 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  CAS  PubMed  PubMed Central  Google Scholar 

  66. Paul J, et al. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and-independent activation of NF-κB and AKT. Cancer Cell. 2017;31(1):64–78.

    Article  CAS  PubMed  Google Scholar 

  67. Lin T, et al. PILLAR-2: a randomized, double-blind, placebo-controlled, phase III study of adjuvant everolimus in poor-risk diffuse large B-cell lymphoma (DLBCL). Proc Am Soc Clin Oncol. 2012.

    Google Scholar 

  68. Carracedo A, Pandolfi P. The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27(41):5527–41.

    Article  CAS  PubMed  Google Scholar 

  69. 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. 2013;110(30):12420–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dreyling M, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Paul J, et al. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and-independent activation of NF-κB and AKT. Cancer Cell. 2017;31(1):64–78.

    Article  CAS  PubMed  Google Scholar 

  72. Erdmann T, et al. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017;130(3):310–22.

    Article  CAS  PubMed  Google Scholar 

  73. Schmitz R, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cummin TE, Du M, Johnson PW. Genetics of diffuse large B-cell lymphoma. N Engl J Med. 2018;379(5):493–4.

    Article  PubMed  Google Scholar 

  76. Shaw AT, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.

    Article  CAS  PubMed  Google Scholar 

  77. Rimokh R, et al. A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). Br J Haematol. 1989;71(1):31–6.

    Article  CAS  PubMed  Google Scholar 

  78. Stein H, et al. CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000;96(12):3681–95.

    CAS  PubMed  Google Scholar 

  79. Passerini CG, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase–positive lymphoma patients. J Natl Cancer Inst. 2014;106(2):djt378.

    Google Scholar 

  80. ALEX. randomised phase III ALEX. 2017. http://www.roche.com/media/store/releases/med-cor-2017-04-10.htm.

  81. Béguelin W, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23(5):677–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. McCabe MT, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492(7427):108–12.

    Article  CAS  PubMed  Google Scholar 

  83. ASH Lymphoma Biology Meeting Report. http://www.epizyme.com/wp-content/uploads/2016/06/EPZM-ASH-L-Data-PR-20160619.pdf.

  84. Assouline SE, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016;128(2):185–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Love C, et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012;44(12):1321–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schmitz R, et al. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med. 2014;4(2):a014282.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Schmitz R, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490(7418):116–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Spender LC, Inman GJ. Phosphoinositide 3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt9s lymphoma cells to BH3 mimetics. Mol Cancer Res. 2012;10:347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Schmitz N, de Leval L. How I manage peripheral T-cell lymphoma, not otherwise specified and angioimmunoblastic T-cell lymphoma: current practice and a glimpse into the future. Br J Haematol. 2017;176(6):851–66.

    Article  CAS  PubMed  Google Scholar 

  90. Itzykson R, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25(7):1147–52.

    Article  CAS  PubMed  Google Scholar 

  91. Delarue R, et al. Treatment with hypomethylating agent 5-Azacytidine induces sustained response in angioimmunoblastic T cell lymphomas. Blood. 2016;128:4164.

    Google Scholar 

  92. Reddy A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481–494.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sartorius UA, Krammer PH. Upregulation of bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer. 2002;97(5):584–92.

    Article  CAS  PubMed  Google Scholar 

  94. Michels J, et al. MCL-1 dependency of cisplatin-resistant cancer cells. Biochem Pharmacol. 2014;92(1):55–61.

    Article  CAS  PubMed  Google Scholar 

  95. Strasser A. The roles of programmed cell death in tumor development and cancer therapy. Medicographia. 2014;36:311–8.

    Google Scholar 

  96. Roberts AW, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.

    Article  CAS  PubMed  Google Scholar 

  97. Choudhary G, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6(1):e1593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Certo M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9(5):351–65.

    Article  CAS  PubMed  Google Scholar 

  99. Gregory G, et al. CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia. 2015;29(6):1437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300–9.

    Article  CAS  PubMed  Google Scholar 

  101. Armand P, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34(31):3733–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.

    Article  PubMed  CAS  Google Scholar 

  103. Green MR, 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. 2010;116(17):3268–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shi M, et al. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am J Surg Pathol. 2014;38(12):1715.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Chapuy B, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nayak L, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017;129(23):3071–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lesokhin AM, et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Blood. 2014;124(21):291.

    Google Scholar 

  108. Gajewski TF, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol. 2013;25(2):268–76.

    Article  CAS  PubMed  Google Scholar 

  109. Andorsky DJ, et al. Programmed death ligand 1 is expressed by non–Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17(13):4232–44.

    Article  CAS  PubMed  Google Scholar 

  110. Rossille D, et al. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-cell lymphoma: results from a French multicenter clinical trial. Leukemia. 2014;28(12):2367–75.

    Article  CAS  PubMed  Google Scholar 

  111. Shipp MA. Gianni BONADONNA memorial lecture: “genetic signatures and targetable pathways in lymphoid malignancies”. Hematol Oncol. 2017;35:23–4.

    Article  Google Scholar 

  112. Abu-Eid R, et al. Selective inhibition of regulatory T cells by targeting the PI3K–Akt pathway. Cancer Immunol Res. 2014;2(11):1080–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Christofides A, et al. Epigenetic regulation of cancer biology and anti-tumor immunity by EZH2. Oncotarget. 2016;7(51):85624–40.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Patton DT, et al. Cutting edge: the phosphoinositide 3-kinase p110δ is critical for the function of CD4+ CD25+ Foxp3+ regulatory T cells. J Immunol. 2006;177(10):6598–602.

    Article  CAS  PubMed  Google Scholar 

  115. Gunderson AJ, et al. Bruton tyrosine kinase–dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 2016;6(3):270–85.

    Article  CAS  PubMed  Google Scholar 

  116. Turaj AH, et al. Antibody tumor targeting is enhanced by CD27 agonists through myeloid recruitment. Cancer Cell. 2017;32(6):777–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Roschewski M, et al. Comparative study of circulating tumor DNA and computerized tomography monitoring in untreated diffuse large B-cell lymphoma. Lancet Oncol. 2015;16(5):541.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Kurtz DM, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol. 2018;36(28):2845–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Scherer F, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med. 2016;8(364):364ra155.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Rossi D, et al. Diffuse large B-cell lymphoma genotyping on the liquid biopsy. Blood. 2017;129(14):1947–57.

    Article  CAS  PubMed  Google Scholar 

  121. Thierry A, et al. Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment. Ann Oncol. 2017;28:2149.

    Article  CAS  PubMed  Google Scholar 

  122. Scherer F, et al. Noninvasive molecular subtyping and risk stratification of DLBCL. Proc Am Soc Clin Oncol. 2016.

    Google Scholar 

  123. Jin MC, et al. Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma. Proc Am Soc Clin Oncol. 2017.

    Google Scholar 

  124. Prasad V. Perspective: the precision-oncology illusion. Nature. 2016;537(7619):S63.

    Article  CAS  PubMed  Google Scholar 

  125. Papadimitrakopoulou V, et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(30):3638–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research UK Centre, University of Southampton, Southampton, UK

    T. E. C. Cummin & P. W. M. Johnson

  2. Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK

    M. S. Cragg

  3. Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA

    J. W. Friedberg

Authors
  1. T. E. C. Cummin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. S. Cragg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. W. Friedberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. W. M. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. W. Friedberg .

Editor information

Editors and Affiliations

  1. Department of Translational Oncology, University-Hospital Münster, Münster, Germany

    Georg Lenz

  2. Department of Hematology, University Claude Bernard Lyon 1, Pierre-Benite cedex, France

    Gilles Salles

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Cummin, T.E.C., Cragg, M.S., Friedberg, J.W., Johnson, P.W.M. (2019). Targeted Therapeutics for Lymphoma: Using Biology to Inform Treatment. In: Lenz, G., Salles, G. (eds) Aggressive Lymphomas. Hematologic Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-00362-3_18

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-00362-3_18

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-00361-6

  • Online ISBN: 978-3-030-00362-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation