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.

Treatment resistance in diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease and represents the most common subtype of lymphoma. Although 60–70% of all patients can be cured by the current standard of care in the frontline setting, the majority of the remaining patients will experience treatment resistance and have a poor clinical outcome. Numerous efforts have been made to improve the efficacy of the standard regimen by, for example, dose intensification or adding novel agents. However, these results generally failed to demonstrate significant clinical benefits. Hence, understanding treatment resistance is a pressing need to optimize the outcome of those patients. In this Review, we first describe the conceptual sources of treatment resistance in DLBCL and then provide detailed and up-to-date molecular insight into the mechanisms of resistance to the current treatment options in DLBCL. We lastly highlight the potential strategies for rationally managing treatment resistance from both the preventive and interventional perspectives.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Sources of treatment resistance in DLBCL.
Fig. 2: Managing treatment resistance in DLBCL.

References

  1. 1.

    Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. Cancer J Clin. 2016;66:443–59.

    Article  Google Scholar 

  2. 2.

    Ennishi D, Hsi ED, Steidl C, Scott DW. Toward a new molecular taxonomy of diffuse large B-cell lymphoma. Cancer Discov. 2020;10:1267–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, 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. 2010;116:2040–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, 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. 2011;12:1013–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Olszewski AJ, Mantripragada KC, Castillo JJ. Risk factors for early death after rituximab-based immunochemotherapy in older patients with diffuse large B-cell lymphoma. J Natl Compr Canc Netw. 2016;14:1121–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile J-F, Castaigne S, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12:460–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, 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;378:1858–67.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  9. 9.

    Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, 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;381:1817–26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013;14:525–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Bartlett NL, Wilson WH, Jung S-H, Hsi ED, Maurer MJ, Pederson LD, et al. Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III intergroup trial alliance/CALGB 50303. J Clin Oncol. 2019;37:1790–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299–309.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA. 2003;100:9991–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl J Med. 2008;359:2313–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl J Med. 2002;346:1937–47.

    PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Herrera AF, Mei M, Low L, Kim HT, Griffin GK, Song JY, et al. Relapsed or refractory double-expressor and double-hit lymphomas have inferior progression-free survival after autologous stem-cell transplantation. J Clin Oncol. 2017;35:24–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Miura K, Takahashi H, Nakagawa M, Izu A, Sugitani M, Kurita D, et al. Clinical significance of co-expression of MYC and BCL2 protein in aggressive B-cell lymphomas treated with a second line immunochemotherapy. Leuk Lymphoma. 2016;57:1335–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Li L, Li Y, Que X, Gao X, Gao Q, Yu M, et al. Prognostic significances of overexpression MYC and/or BCL2 in R-CHOP-treated diffuse large B-cell lymphoma: A Systematic review and meta-analysis. Sci Rep. 2018;8:6267.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Ennishi D, Mottok A, Ben-Neriah S, Shulha HP, Farinha P, Chan FC, et al. Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. Blood. 2017;129:2760–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA. 2012;109:3879–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    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;171:481–94.e15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Wright GW, Huang DW, Phelan JD, Coulibaly ZA, Roulland S, Young RM, et al. A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications. Cancer Cell. 2020;37:551–68.e14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    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;24:679–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    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;378:1396–407.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Lacy SE, Barrans SL, Beer PA, Painter D, Smith AG, Roman E, et al. Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report. Blood. 2020;135:1759–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Melchardt T, Hufnagl C, Weinstock DM, Kopp N, Neureiter D, Tränkenschuh W, et al. Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones. Oncotarget. 2016;7:51494–502.

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Rushton CK, Arthur SE, Alcaide M, Cheung M, Jiang A, Coyle KM, et al. Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma. Blood Adv. 2020;4:2886–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Morin RD, Assouline S, Alcaide M, Mohajeri A, Johnston RL, Chong L, et al. Genetic landscapes of relapsed and refractory diffuse large B-cell lymphomas. Clin Cancer Res. 2016;22:2290–300.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Wise JF, Nakken S, Steen CB, Vodák D, Trøen G, Johannessen B, et al. Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series. Blood Adv. 2020;4:1859–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Juskevicius D, Lorber T, Gsponer J, Perrina V, Ruiz C, Stenner-Liewen F, et al. Distinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome-wide copy number aberration and targeted sequencing analysis. Leukemia. 2016;30:2385–95.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Jardin F, Jais J-P, Molina T-J, Parmentier F, Picquenot J-M, Ruminy P, et al. Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study. Blood. 2010;116:1092–104.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Challa-Malladi M, Lieu YK, Califano O, Holmes AB, Bhagat G, Murty VV, et al. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell. 2011;20:728–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Chambwe N, Kormaksson M, Geng H, De S, Michor F, Johnson NA, et al. Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes. Blood. 2014;123:1699–708.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Pan H, Jiang Y, Boi M, Tabbò F, Redmond D, Nie K, et al. Epigenomic evolution in diffuse large B-cell lymphomas. Nat Commun. 2015;6:6921.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346–54.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Lwin T, Hazlehurst LA, Li Z, Dessureault S, Sotomayor E, Moscinski LC, et al. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkin’s lymphoma cells. Leukemia. 2007;21:1521–31.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Lwin T, Lin J, Choi YS, Zhang X, Moscinski LC, Wright KL, et al. Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA-181a. Blood. 2010;116:5228–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Lwin T, Zhao X, Cheng F, Zhang X, Huang A, Shah B, et al. A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J Clin Investig. 2013;123:4612–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Lwin T, Crespo LA, Wu A, Dessureault S, Shu HB, Moscinski LC, et al. Lymphoma cell adhesion-induced expression of B cell-activating factor of the TNF family in bone marrow stromal cells protects non-Hodgkin’s B lymphoma cells from apoptosis. Leukemia. 2009;23:170–7.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Linderoth J, Edén P, Ehinger M, Valcich J, Jerkeman M, Bendahl P-O, et al. Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma. Br J Haematol. 2008;141:423–32.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Fornecker L-M, Muller L, Bertrand F, Paul N, Pichot A, Herbrecht R, et al. Multi-omics dataset to decipher the complexity of drug resistance in diffuse large B-cell lymphoma. Sci Rep. 2019;9:895.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Xu-Monette ZY, Xiao M, Au Q, Padmanabhan R, Xu B, Hoe N, et al. Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL. Cancer Immunol Res. 2019;7:644–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Müller C, Murawski N, Wiesen MHJ, Held G, Poeschel V, Zeynalova S, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119:3276–84.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  47. 47.

    Pfreundschuh M, Müller C, Zeynalova S, Kuhnt E, Wiesen MHJ, Held G, et al. Suboptimal dosing of rituximab in male and female patients with DLBCL. Blood. 2014;123:640–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Rozman S, Grabnar I, Novaković S, Mrhar A, Jezeršek, Novaković B. Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome. Br J Clin Pharm. 2017;83:1782–90.

    CAS  Article  Google Scholar 

  49. 49.

    Pfreundschuh M, Murawski N, Zeynalova S, Ziepert M, Loeffler M, Hänel M, et al. Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients. Br J Haematol. 2017;179:410–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Ghesquieres H, Slager SL, Jardin F, Veron AS, Asmann YW, Maurer MJ, et al. Genome-wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2015;33:3930–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Palmer AC, Chidley C, Sorger PK. A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity. Elife. 2019;8:e50036.

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Zou L, Song G, Gu S, Kong L, Sun S, Yang L, et al. Mechanism and treatment of rituximab resistance in diffuse large B-cell lymphoma. Curr Cancer Drug Targets. 2019;19:681–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Due H, Schönherz AA, Ryø L, Primo MN, Jespersen DS, Thomsen EA, et al. MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma. Blood Adv. 2019;3:1185–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Marques SC, Ranjbar B, Laursen MB, Falgreen S, Bilgrau AE, Bødker JS, et al. High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma. Exp Hematol. 2016;44:238–46.e2.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Feng Y, Zhong M, Zeng S, Wang L, Liu P, Xiao X, et al. Exosome-derived miRNAs as predictive biomarkers for diffuse large B-cell lymphoma chemotherapy resistance. Epigenomics. 2019;11:35–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Chen J, Ge X, Zhang W, Ding P, Du Y, Wang Q, et al. PI3K/AKT inhibition reverses R-CHOP resistance by destabilizing SOX2 in diffuse large B cell lymphoma. Theranostics. 2020;10:3151–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Barré FPY, Claes BSR, Dewez F, Peutz-Kootstra C, Munch-Petersen HF, Grønbæk K, et al. Specific lipid and metabolic profiles of R-CHOP-resistant diffuse large B-cell lymphoma elucidated by matrix-assisted laser desorption ionization mass spectrometry imaging and in vivo imaging. Anal Chem. 2018;90:14198–206.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Ennishi D, Healy S, Bashashati A, Saberi S, Hother C, Mottok A, et al. TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma. Nat Med. 2020;26:577–88.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    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;42:181–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Yap DB, Chu J, Berg T, Schapira M, Cheng S-WG, 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;117:2451–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, 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. 2010;107:20980–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677–92.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Morschhauser F, Salles G, McKay P, Tilly H, Schmitt A, Gerecitano J, 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 

  64. 64.

    Brach D, Johnston-Blackwell D, Drew A, Lingaraj T, Motwani V, Warholic NM, et al. EZH2 inhibition by tazemetostat results in altered dependency on B-cell activation signaling in DLBCL. Mol Cancer Ther. 2017;16:2586–97.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    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;492:108–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Bisserier M, Wajapeyee N. Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas. Blood. 2018;131:2125–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Baker T, Nerle S, Pritchard J, Zhao B, Rivera VM, Garner A, et al. Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors. Oncotarget. 2015;6:32646–55.

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Gibaja V, Shen F, Harari J, Korn J, Ruddy D, Saenz-Vash V, et al. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene. 2016;35:558–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Tula-Sanchez AA, Havas AP, Alonge PJ, Klein ME, Doctor SR, Pinkston W, et al. A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors. Cancer Biol Ther. 2013;14:949–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Joosten M, Ginzel S, Blex C, Schmidt D, Gombert M, Chen C, et al. A novel approach to detect resistance mechanisms reveals FGR as a factor mediating HDAC inhibitor SAHA resistance in B-cell lymphoma. Mol Oncol. 2016;10:1232–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Mondello P, Tadros S, Teater M, Fontan L, Chang AY, Jain N, et al. Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma. Cancer Disco. 2020;10:440–59.

    CAS  Article  Google Scholar 

  72. 72.

    Meyer SN, Scuoppo C, Vlasevska S, Bal E, Holmes AB, Holloman M, et al. Unique and shared epigenetic programs of the CREBBP and EP300 acetyltransferases in germinal center B cells reveal targetable dependencies in lymphoma. Immunity. 2019;51:535–47.e9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature. 2018;560:387–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Fox LC, Yannakou CK, Ryland G, Lade S, Dickinson M, Campbell BA, et al. Molecular mechanisms of disease progression in primary cutaneous diffuse large B-cell lymphoma, leg type during ibrutinib therapy. Int J Mol Sci. 2018;19:1758.

  77. 77.

    Woyach JA, Furman RR, Liu T-M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N. Engl J Med. 2014;370:2286–94.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Chen JG, Liu X, Munshi M, Xu L, Tsakmaklis N, Demos MG, et al. BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism. Blood. 2018;131:2047–59.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Choi J, Phelan JD, Wright GW, Häupl B, Huang DW, Shaffer AL 3rd, et al. Regulation of B cell receptor-dependent NF-κB signaling by the tumor suppressor KLHL14. Proc Natl Acad Sci USA. 2020;117:6092–102.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Jain N, Singh S, Laliotis G, Hart A, Muhowski E, Kupcova K, et al. Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma. Blood Adv. 2020;4:4382–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Uddin S, Hussain AR, Siraj AK, Manogaran PS, Al-Jomah NA, Moorji A, et al. Role of phosphatidylinositol 3’-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood. 2006;108:4178–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Wang X, Cao X, Sun R, Tang C, Tzankov A, Zhang J, et al. Clinical significance of PTEN deletion, mutation, and loss of PTEN expression in de novo diffuse large B-cell lymphoma. Neoplasia. 2018;20:574–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Pfeifer M, Grau M, Lenze D, Wenzel S-S, Wolf A, Wollert-Wulf B, et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA. 2013;110:12420–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Chen L, Ouyang J, Wienand K, Bojarczuk K, Hao Y, Chapuy B, et al. CXCR4 upregulation is an indicator of sensitivity to B-cell receptor/PI3K blockade and a potential resistance mechanism in B-cell receptor-dependent diffuse large B-cell lymphomas. Haematologica. 2020;105:1361–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, et al. Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010;28:4740–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Eyre TA, Hildyard C, Hamblin A, Ali AS, Houlton A, Hopkins L, et al. A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL. Hematol Oncol. 2019;37:352–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Eyre TA, Collins GP, Goldstone AH, Cwynarski K. Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies. Br J Haematol. 2014;166:336–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, 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. 2012;30:3452–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    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;19:202–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    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;35:826–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Choudhary GS, Al-harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, 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:e1593–e1593.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Adams CM, Mitra R, Gong JZ, Eischen CM. Non-Hodgkin and Hodgkin lymphomas select for overexpression of BCLW. Clin Cancer Res. 2017;23:7119–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010;115:3304–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018;131:68–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a Phase Ib study. J Clin Oncol. 2016;34:2698–704.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Ansell SM, Minnema MC, Johnson P, Timmerman JM, Armand P, Shipp MA, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: a single-arm, Phase II study. J Clin Oncol. 2019;37:481–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Godfrey J, Tumuluru S, Bao R, Leukam M, Venkataraman G, Phillip J, et al. PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype. Blood. 2019;133:2279–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl J Med. 2019;380:45–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl J Med. 2017;377:2531–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839–52.

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Kochenderfer JN, Somerville RPT, Lu T, Yang JC, Sherry RM, Feldman SA, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther. 2017;25:2245–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Shalabi H, Kraft IL, Wang H-W, Yuan CM, Yates B, Delbrook C, et al. Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma. Haematologica. 2018;103:e215–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl J Med. 2017;377:2545–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Zhang Z, Chen X, Tian Y, Li F, Zhao X, Liu J, et al. Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy. J Immunother Cancer. 2020;8:e001150.

    PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Dufva O, Koski J, Maliniemi P, Ianevski A, Klievink J, Leitner J, et al. Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity. Blood. 2020;135:597–609.

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Jain MD, Zhao H, Wang X, Atkins R, Menges M, Reid K, et al. Tumor interferon signaling and suppressive myeloid cells associate with CAR T cell failure in large B cell lymphoma. Blood. 2021;137:2621–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Deng Q, Han G, Puebla-Osorio N, Ma MCJ, Strati P, Chasen B, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020;26:1878–87.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  108. 108.

    Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, 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;117:5058–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113:6069–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Crump M, Leppä S, Fayad L, Lee JJ, Di Rocco A, Ogura M, et al. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J Clin Oncol. 2016;34:2484–92.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Hainsworth JD, Arrowsmith ER, McCleod M, Hsi ED, Hamid O, Shi P, et al. A randomized, phase 2 study of R-CHOP plus enzastaurin vs R-CHOP in patients with intermediate- or high-risk diffuse large B-cell lymphoma. Leuk Lymphoma. 2016;57:216–8.

    PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Nowakowski GS, Zhu J, Zhang Q, Brody J, Sun X, Maly J, et al. ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1. Future Oncol. 2020;16:991–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Roider T, Seufert J, Uvarovskii A, Frauhammer F, Bordas M, Abedpour N, et al. Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels. Nat Cell Biol. 2020;22:896–906.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity. 2018;49:178–93.e7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, et al. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019;133:1876–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Kurtz DM, Scherer F, Jin MC, Soo J, Craig AFM, Esfahani MS, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol. 2018;36:2845–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Scherer F, Kurtz DM, Newman AM, Stehr H, Craig AFM, Esfahani MS, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med. 2016;8:364ra155.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Rossi D, Diop F, Spaccarotella E, Monti S, Zanni M, Rasi S, et al. Diffuse large B-cell lymphoma genotyping on the liquid biopsy. Blood. 2017;129:1947–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Roschewski M, Dunleavy K, Pittaluga S, Moorhead M, Pepin F, Kong K, et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol. 2015;16:541–9.

    PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Kurtz DM, Esfahani MS, Scherer F, Soo J, Jin MC, Liu CL, et al. Dynamic risk profiling using serial tumor biomarkers for personalized outcome prediction. Cell. 2019;178:699–713.e19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    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;3:1002–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    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;130:192–192.

    Article  CAS  Google Scholar 

  123. 123.

    Mathur R, Sehgal L, Havranek O, Köhrer S, Khashab T, Jain N, et al. Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs. Haematologica. 2017;102:373–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Facciotto C, Casado J, Turunen L, Leivonen S-K, Tumiati M, Rantanen V, et al. Drug screening approach combines epigenetic sensitization with immunochemotherapy in cancer. Clin Epigenetics. 2019;11:192.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Sagiv-Barfi I, Kohrt HEK, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA. 2015;112:E966–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Disco. 2018;8:216–33.

    CAS  Article  Google Scholar 

  128. 128.

    Bouwstra R, He Y, de Boer J, Kooistra H, Cendrowicz E, Fehrmann RSN, et al. CD47 expression defines efficacy of rituximab with CHOP in non-germinal center B-cell (Non-GCB) diffuse large b-cell lymphoma patients (DLBCL), but not in GCB DLBCL. Cancer Immunol Res. 2019;7:1663–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142:699–713.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N. Engl J Med. 2018;379:1711–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immune-oncology. Nat Rev Cancer. 2019;19:151–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

The writing of this manuscript was supported by Genome Canada, the Ontario Research Fund, the Leukemia & Lymphoma Society of Canada, the Princess Margaret Cancer Centre and the Princess Margaret Cancer Foundation. Preparation of the figures was aided with BioRender.com.

Author information

Affiliations

Authors

Contributions

All authors made substantial contributions to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Robert Kridel.

Ethics declarations

Conflict of interest

MYH declares no conflict of interest. RK reports research funding from Gilead Sciences and Roche.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

He, M.Y., Kridel, R. Treatment resistance in diffuse large B-cell lymphoma. Leukemia 35, 2151–2165 (2021). https://doi.org/10.1038/s41375-021-01285-3

Download citation

Search

Quick links