Skip to main content

Therapeutic Modulators of Apoptosis and Epigenetics in Aggressive Lymphoma

  • Chapter
  • First Online:
Aggressive Lymphomas

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

  • 842 Accesses

Abstract

Elsewhere throughout this text, other authors have discussed the role of targeted immunotherapies, small molecules targeting the B-cell receptor complex and tyrosine kinases that regulate cellular function. In this chapter we address other small molecules that target cellular signalling pathways involved in malignant cell survival, not otherwise addressed in this book.

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

Access this chapter

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. Cory S, Roberts AW, Colman PM, Adams JM. Targeting BCL-2-like proteins to kill cancer cells. Trends Cancer. 2016;2(8):443–60.

    Article  PubMed  Google Scholar 

  2. Roberts AW, Huang D. Targeting BCL2 with BH3 mimetics: basic science and clinical application of Venetoclax in chronic lymphocytic leukemia and related malignancies. Clin Pharmacol Ther. 2017;101(1):89–98.

    Article  CAS  PubMed  Google Scholar 

  3. Hermine O, Haioun C, Lepage E, d’Agay MF, Briere J, Lavignac C, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 1996;87(1):265–72.

    CAS  PubMed  Google Scholar 

  4. Gascoyne RD, Adomat SA, Krajewski S, Krajewska M, Horsman DE, Tolcher AW, et al. Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin’s lymphoma. Blood. 1997;90(1):244–51.

    CAS  PubMed  Google Scholar 

  5. Winter JN, Andersen J, Reed JC, Krajewski S, Variakojis D, Bauer KD, et al. BCL-2 expression correlates with lower proliferative activity in the intermediate- and high-grade non-Hodgkin’s lymphomas: an Eastern Cooperative Oncology Group and Southwest Oncology Group Cooperative Laboratory Study. Blood. 1998;91(4):1391–8.

    CAS  PubMed  Google Scholar 

  6. Friedberg JW. Double-hit diffuse large B-cell lymphoma. J Clin Oncol. 2012;30(28):3439–43.

    Article  CAS  PubMed  Google Scholar 

  7. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, 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. 2012;30(28):3460–7.

    Article  CAS  PubMed  Google Scholar 

  8. Pedersen MO, Gang AO, Poulsen TS, Knudsen H, Lauritzen AF, Nielsen SL, et al. Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma—a single centre’s experience. Eur J Haematol. 2012;89(1):63–71.

    Article  PubMed  Google Scholar 

  9. Landsburg DJ, Nasta SD, Svoboda J, Morrissette JJ, Schuster SJ. ‘Double-Hit’ cytogenetic status may not be predicted by baseline clinicopathological characteristics and is highly associated with overall survival in B cell lymphoma patients. Br J Haematol. 2014;166(3):369–74.

    Article  CAS  PubMed  Google Scholar 

  10. Landsburg DJ, Petrich AM, Abramson JS, Sohani AR, Press O, Cassaday R, et al. Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma. Cancer. 2016;122(4):559–64.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488–96.

    Article  CAS  PubMed  Google Scholar 

  13. Kipps TJ, Eradat H, Grosicki S, Catalano J, Cosolo W, Dyagil IS, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(10):2826–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128(6):1173–86.

    Article  CAS  PubMed  Google Scholar 

  15. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, 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 

  16. Roberts AW, Stilgenbauer S, Seymour JF, Huang DCS. Venetoclax in patients with previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2017;23(16):4527–33.

    Article  CAS  PubMed  Google Scholar 

  17. Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016;127(25):3215–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Anderson MA, Tam C, Lew TE, Juneja S, Juneja M, Westerman D, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129(25):3362–70.

    CAS  PubMed  Google Scholar 

  19. Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, 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 

  20. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, et al. Venetoclax-Rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20.

    Article  CAS  PubMed  Google Scholar 

  21. Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, et al. Ibrutinib plus Venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211–23.

    Article  CAS  PubMed  Google Scholar 

  22. Zelenetz AD, Salles GA, Mason KD, Casulo C, Gouill SL, Sehn LH, et al. Phase 1b study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma. J Clin Oncol. 2016;34.(15_suppl:7566.

    Article  Google Scholar 

  23. Zelenetz AD, Salles GA, Mason KD, Casulo C, Le Gouill S, Sehn LH, et al. Results of a Phase Ib study of Venetoclax Plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma. Blood. 2016;128:3032.

    Google Scholar 

  24. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dawson MA, Kouzarides T, Huntly BJ. Targeting epigenetic readers in cancer. N Engl J Med. 2012;367(7):647–57.

    Article  CAS  PubMed  Google Scholar 

  26. Bertrand P. Inside HDAC with HDAC inhibitors. Eur J Med Chem. 2010;45(6):2095–116.

    Article  CAS  PubMed  Google Scholar 

  27. Dickinson M, Johnstone RW, Prince HM. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs. 2010;28(Suppl 1):S3–20.

    Article  PubMed  CAS  Google Scholar 

  28. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769–84.

    Article  CAS  PubMed  Google Scholar 

  29. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631–6.

    Article  CAS  PubMed  Google Scholar 

  30. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):5827–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Foss F, Pro B, Miles Prince H, Sokol L, Caballero D, Horwitz S, et al. Responses to romidepsin by line of therapy in patients with relapsed or refractory peripheral T-cell lymphoma. Cancer Med. 2017;6(1):36–44.

    Article  CAS  PubMed  Google Scholar 

  33. Dupuis J, Morschhauser F, Ghesquieres H, Tilly H, Casasnovas O, Thieblemont C, et al. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Lancet Haematol. 2015;2(4):e160–5.

    Article  PubMed  Google Scholar 

  34. O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30(18):2197–203.

    Article  CAS  PubMed  Google Scholar 

  36. Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M, Neelapu S, et al. Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2011;12(13):1222–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, 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 

  38. Bishton MJ, Harrison SJ, Martin BP, McLaughlin N, James C, Josefsson EC, et al. Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. Blood. 2011;117(13):3658–68.

    Article  CAS  PubMed  Google Scholar 

  39. Cabell C, Bates S, Piekarz R, Whittaker S, Kim Y, Godfrey C, et al. Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin. ASCO Meeting Abstr. 2009;27(15S):e19533 EP.

    Google Scholar 

  40. Pohlman B, Advani R, Duvic M, Hymes K, Intragumtornchai T, Lekhakula A, et al. Final results of a phase II trial of Belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-cell lymphoma. ASH Annual Meeting Abstr. 2009;114(22):920 EP.

    Google Scholar 

  41. Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W. The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia. 2014;28(3):485–96.

    Article  CAS  PubMed  Google Scholar 

  42. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, 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 

  43. Couronne L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med. 2012;366(1):95–6.

    Article  CAS  PubMed  Google Scholar 

  44. Lemonnier F, Couronne L, Parrens M, Jais JP, Travert M, Lamant L, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120(7):1466–9.

    Article  CAS  PubMed  Google Scholar 

  45. Van Arnam JS, Lim MS, Elenitoba-Johnson KSJ. Novel insights into the pathogenesis of T-cell lymphomas. Blood. 2018.

    Google Scholar 

  46. Fujisawa M, Sakata-Yanagimoto M, Nishizawa S, Komori D, Gershon P, Kiryu M, et al. Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. Leukemia. 2018;32(3):694–702.

    Article  CAS  PubMed  Google Scholar 

  47. Muto H, Sakata-Yanagimoto M, Nagae G, Shiozawa Y, Miyake Y, Yoshida K, et al. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. Blood Cancer J. 2014;4:e264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Saillard C, Guermouche H, Derrieux C, Bruneau J, Frenzel L, Couronne L, et al. Response to 5-azacytidine in a patient with TET2-mutated angioimmunoblastic T-cell lymphoma and chronic myelomonocytic leukaemia preceded by an EBV-positive large B-cell lymphoma. Hematol Oncol. 2017;35(4):864–8.

    Article  CAS  PubMed  Google Scholar 

  49. Cheminant M, Bruneau J, Kosmider O, Lefrere F, Delarue R, Gaulard P, et al. Efficacy of 5-azacytidine in a TET2 mutated angioimmunoblastic T cell lymphoma. Br J Haematol. 2015;168(6):913–6.

    Article  CAS  PubMed  Google Scholar 

  50. Moreno A, Szmania S, Shi J, Barlogie B, Prentice G, van Rhee F. Induction of the cancer-testis antigen MAGE-A3 in myeloma cell lines by 5'azacitidine and MGCD0103. ASCO Meeting Abstr. 2008;26(15_suppl):14008.

    Google Scholar 

  51. Goodyear O, Agathanggelou A, Ryan G, Novitsky-Basso I, Stankovic T, Moss P, et al. The epigenetic therapies Azacitidine and Sodium Valproate augment immune responses to the MAGE cancer testis antigen in acute myeloid leukemia and myeloma. ASH Annual Meeting Abstr. 2009;114(22):2086 EP.

    Google Scholar 

  52. Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G, et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116(11):1908–18.

    Article  CAS  PubMed  Google Scholar 

  53. Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5(3):587–98.

    PubMed  PubMed Central  Google Scholar 

  54. Toor AA, Payne KK, Chung HM, Sabo RT, Hazlett AF, Kmieciak M, et al. Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen-specific cellular immunity. Br J Haematol. 2012;158(6):700–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Clozel T, Yang S, Elstrom RL, Tam W, Martin P, Kormaksson M, et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 2013;3(9):1002–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Moss JJ, Howard D, Van Meter E, Hayslip J. A phase I study of the combination of Azacitidine, Cyclophosphamide, Vincristine, and Rituximab in relapsed and refractory lymphoma. Blood. 2011;118:1624.

    Google Scholar 

  57. Martin P, Bartlett NL, Rivera IIR, Revuelta M, Chavez JC, Reagan JL, et al. A phase I, open label, multicenter trial of oral Azacitidine (CC-486) Plus R-CHOP in patients with high-risk, previously untreated diffuse large B-cell lymphoma, Grade 3B follicular lymphoma, or transformed lymphoma. Blood. 2017;130:192.

    Article  CAS  Google Scholar 

  58. Laille E, Shi T, Garcia-Manero G, Cogle CR, Gore SD, Hetzer J, et al. Pharmacokinetics and pharmacodynamics with extended dosing of CC-486 in patients with hematologic malignancies. PLoS One. 2015;10(8):e0135520.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Wang W, Wang J, Li M, Ying J, Jing H. 5-Azacitidine induces demethylation of PTPL1 and inhibits growth in non-Hodgkin lymphoma. Int J Mol Med. 2015;36(3):698–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hiraga J, Tomita A, Suzuki N, Takagi Y, Narita M, Kagami Y. Partial restoration of CD20 protein expression and rituximab sensitivity after treatment with azacitidine in CD20-negative transformed diffuse large B cell lymphoma after using rituximab. Ann Hematol. 2018.

    Google Scholar 

  61. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117(8):2451–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ryan RJ, Nitta M, Borger D, Zukerberg LR, Ferry JA, Harris NL, et al. EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas. PLoS One. 2011;6(12):e28585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bodor C, O'Riain C, Wrench D, Matthews J, Iyengar S, Tayyib H, et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia. 2011;25(4):726–9.

    Article  CAS  PubMed  Google Scholar 

  65. Velichutina I, Shaknovich R, Geng H, Johnson NA, Gascoyne RD, Melnick AM, et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood. 2010;116(24):5247–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42(8):665–7.

    Article  CAS  PubMed  Google Scholar 

  67. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012;109(52):21360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, 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 

  70. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8(11):890–6.

    Article  CAS  PubMed  Google Scholar 

  71. Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, et al. B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018;19(5):649–59.

    Article  CAS  PubMed  Google Scholar 

  72. Wire GN. Epizyme announces Tazemetostat fast track designation for follicular lymphoma and plenary session on Phase 2 NHL data at ICML 2017. https://globenewswire.com/news-release/2017/04/25/970819/0/en/Epizyme-Announces-Tazemetostat-Fast-Track-Designation-for-Follicular-Lymphoma-and-Plenary-Session-on-Phase-2-NHL-Data-at-ICML.html. Accessed 10 Jan 2018.

  73. Morschhauser F, Salles G, McKay P, Tilly H, Schmitt A, Gerecitano J, et al. Interim report from phase 2 multicentre study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B cell non-Hodgkin lymphomas. 2017. http://www.epizyme.com/wp-content/uploads/2017/06/ICML-Tazemetostat-F-Morschhauser-FINAL-2.pdf.

  74. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res. 2015;21(7):1628–38.

    Article  CAS  PubMed  Google Scholar 

  76. Amorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3(4):e196–204.

    Article  PubMed  Google Scholar 

  77. Dawson M, Stein EM, Huntly BJP, Karadimitris A, Kamdar M, Fernandez de Larrea C, et al. A phase I study of GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of phase I/II open label single agent study in patients with acute myeloid leukemia (AML). Blood. 2017;130:1377.

    Article  CAS  Google Scholar 

  78. Borthakur G, Dawson MA, Stein EM, Karadimitris A, Huntly BJP, Dickinson MJ, et al. A phase I/II open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in subjects with relapsed, refractory hematologic malignancies. Blood. 2016;128:5223.

    Google Scholar 

  79. Hogg SJ, Newbold A, Vervoort SJ, Cluse LA, Martin BP, Gregory GP, et al. BET inhibition induces apoptosis in aggressive B-cell lymphoma via epigenetic regulation of BCL-2 family members. Mol Cancer Ther. 2016;15(9):2030–41.

    Article  CAS  PubMed  Google Scholar 

  80. Johnson-Farley N, Veliz J, Bhagavathi S, Bertino JR. ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in “double hit” lymphoma cells. Leuk Lymphoma. 2015;56(7):2146–52.

    Article  CAS  PubMed  Google Scholar 

  81. Li Q, Lozano G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res. 2013;19(1):34–41.

    Article  PubMed  CAS  Google Scholar 

  82. Moller MB, Ino Y, Gerdes AM, Skjodt K, Louis DN, Pedersen NT. Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. Leukemia. 1999;13(3):453–9.

    Article  CAS  PubMed  Google Scholar 

  83. Vasmatzis G, Johnson SH, Knudson RA, Ketterling RP, Braggio E, Fonseca R, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120(11):2280–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Solenthaler M, Matutes E, Brito-Babapulle V, Morilla R, Catovsky D. p53 and mdm2 in mantle cell lymphoma in leukemic phase. Haematologica. 2002;87(11):1141–50.

    CAS  PubMed  Google Scholar 

  85. Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS, Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993;82(8):2289–95.

    CAS  PubMed  Google Scholar 

  86. Tzardi M, Kouvidou C, Panayiotides I, Stefanaki K, Rontogianni D, Zois E, et al. p53 protein expression in non-Hodgkin’s lymphoma. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1. Clin Mol Pathol. 1996;49(5):M278–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Xu-Monette ZY, Moller MB, Tzankov A, Montes-Moreno S, Hu W, Manyam GC, et al. MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;122(15):2630–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Drakos E, Singh RR, Rassidakis GZ, Schlette E, Li J, Claret FX, et al. Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). Leukemia. 2011;25(5):856–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Herting F, Herter S, Friess T, Muth G, Bacac M, Sulcova J, et al. Antitumour activity of the glycoengineered type II anti-CD20 antibody obinutuzumab (GA101) in combination with the MDM2-selective antagonist idasanutlin (RG7388). Eur J Haematol. 2016;97(5):461–70.

    Article  CAS  PubMed  Google Scholar 

  90. Herting F, Friess T, Umana P, Middleton S, Klein C. Chemotherapy-free, triple combination of obinutuzumab, venetoclax and idasanutlin: antitumor activity in xenograft models of non-Hodgkin lymphoma. Leuk Lymphoma. 2018;59(6):1482–5.

    Article  CAS  PubMed  Google Scholar 

  91. Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, et al. Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (Pts). Blood. 2014;124(21):116.

    Google Scholar 

  92. Reis B, Jukofsky L, Chen G, Martinelli G, Zhong H, So WV, et al. Acute myeloid leukemia patients’ clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica. 2016;101(5):e185–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, 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 

  94. Karube K, Enjuanes A, Dlouhy I, Jares P, Martin-Garcia D, Nadeu F, et al. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. Leukemia. 2018;32(3):675–84.

    Article  CAS  PubMed  Google Scholar 

  95. Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481–94 e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pasqualucci L, Dalla-Favera R. Genetics of diffuse large B cell lymphoma. Blood. 2018;131(21):2307–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Stathis A, Iasonos A, Seymour JF, Thieblemont C, Ribrag V, Zucca E, et al. Report of the 14th International Conference on Malignant Lymphoma (ICML) closed workshop on future design of clinical trials in lymphomas. Clin Cancer Res. 2018;24(13):2993–8.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John F. Seymour .

Editor information

Editors and Affiliations

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

Dickinson, M.J., Seymour, J.F. (2019). Therapeutic Modulators of Apoptosis and Epigenetics in Aggressive Lymphoma. In: Lenz, G., Salles, G. (eds) Aggressive Lymphomas. Hematologic Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-00362-3_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-00362-3_17

  • 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