Opinion Statement
It has become clear that there is immense biological heterogeneity in diffuse large B cell lymphoma (DLBCL). Developing technology has allowed better characterization of patient subsets at a molecular level, allowing for a link of phenotype and clinical outcomes to oncogenic mechanisms and biologic signatures. Cell of origin and double hit status are able to identify aggressive subsets, with molecular profiling allowing for a clearer understanding of biologic pathways that contribute to cellular resistance to conventional treatment in these subsets. Although the standard treatment for DLBCL remains R-CHOP or R-CHOP-like therapy at present, rational drug targets have been established with novel classes of drugs under investigation. In germinal center (GC) DLBCL, mechanisms of therapeutic interest include anti-apoptosis mediated by BCL-2, PI3K/AKT/mTOR, and EZH2, whereas drug interventions are directed at BCR, NF-κB, and/or JAK-STAT pathways in activated B cell (ABC) DLBCL. There is also evidence for cooperation of various oncogenic pathways in these subsets. As such, we are arguably on the verge of shifting to a more tailored approach using single and combinatorial strategies—this, however, relies on prioritizing the exploration of biomarkers for patient selection for validating novel treatment strategies.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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(12):2040–5.
Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22):5027–33.
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(6769):503–11.
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(22):2313–23.
Pfeifer M, Grau M, Lenze D, Wenzel SS, 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 U S A. 2013;110(30):12420–5.
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(7360):298–303.
Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189–95.
Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat Rev Clin Oncol. 2014;11(1):12–23.
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(6):525–33.
• 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(9880):1817–26. This phase III trial evaluated R-CHOP-14 vs R-CHOP-21 and demonstrated that R-CHOP-14 was not superior to R-CHOP-21 for a primary endpoint of overall survival. The MYC (+) subgroup did not benefit from a dose dense approach
Recher C, Coiffier B, Haioun C, Molina TJ, Ferme 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(9806):1858–67.
Younes A, Zinzani PL, Sehn LH, Johnson PW, Gascoyne RD, Ahmadi T, et al., eds. A randomized, double-blind, placebo-controlled phase 3 study of ibrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in subjects with newly diagnosed nongerminal center B-cell subtype of diffuse large B-cell lymphoma (DLBCL). ASCO Annual Meeting Proceedings.
• Nowakowski GS, La Plant B, Macon WR, Reeder CB, Foran JM, Nelson GD, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol. 2015;33(3):251–7. This phase II study showed that lenalidomide combined with R-CHOP improved clinical outcomes in DLBCL, particularly for patients with non-germinal center subtype DLBCL, as compared to historical rates with R-CHOP alone. This has led to the phase III ROBUST trial of lenalidomide + R-CHOP vs R-CHOP for untreated ABC DLBCL
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.
• Petrich AM, Gandhi M, Jovanovic B, Castillo JJ, Rajguru S, Yang DT, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354–61. This is the largest retrospective multicenter series evaluating the impact of induction regimens and stem cell transplantion on outcomes in double-hit lymphomas, demonstrating improved outcomes with dose-intense regimens over R-CHOP. Transplant was not shown to improve survival in patients achieving CR with frontline therapy.
Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891–901.
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.
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(28):3452–9.
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(7277):88–92.
Young RM, Shaffer 3rd AL, Phelan JD, Staudt LM. B-cell receptor signaling in diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):77–85.
Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem. 2007;2(1):58–61.
Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88–94.
Wilson WH, Gerecitano JF, Goy A, de Vos S, Kenkre VP, Barr PM, 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;120:686.
Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S, et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014;15(9):1019–26.
Mehta-Shah N, Younes A. Novel targeted therapies in diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):126–37.
Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6(1):59.
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13):2578–85.
Flinn IW, Bartlett NL, Blum KA, Ardeshna KM, LaCasce AS, Flowers CR, 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.
Crump M, Leppa 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(21):2484–92.
Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, et al. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget. 2015;6(41):43881–96.
Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861–74.
Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B cell antigen receptor signaling 101. Mol Immunol. 2004;41(6–7):599–613.
Knittel G, Liedgens P, Korovkina D, Seeger JM, Al-Baldawi Y, Al-Maarri M, et al. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood. 2016;127(22):2732–41.
Strauss SJ, Higginbottom K, Juliger S, Maharaj L, Allen P, Schenkein D, et al. The proteasome inhibitor bortezomib acts independently of p53 and induces cell death via apoptosis and mitotic catastrophe in B-cell lymphoma cell lines. Cancer Res. 2007;67(6):2783–90.
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(24):6069–76.
• Leonard JP, Kolibaba K, Reeves JA, Tulpule A, Flinn IW, Kolevska T, et al. Randomized phase 2 open-label study of R-CHOP ± bortezomib in patients (pts) with untreated non-germinal center B-cell-like (non-GCB) subtype diffuse large cell lymphoma (DLBCL): results from the pyramid trial. Blood. 2015;126:811. This phase II trial suggests that there is no benefit to adjunctive bortezomib with R-CHOP for non-germinal center DLBCL, which typically relies on NF-κB signaling. However, questions have been raised as to whether this combination may be more effective if limited to ABC DLBCL subsets, identified specifically by gene-expression profiling
Kelly PN, Romero DL, Yang Y, Shaffer 3rd AL, Chaudhary D, Robinson S, et al. Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J Exp Med. 2015;212(13):2189–201.
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007.
•• Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18. This phase II trial evaluated idelalisib monotherapy in double refractory indolent lymphomas and demonstrated high activity with an overall response rate of 57% and median progression-free survival of 11 months. This pivotal study led to the FDA approval of idelalisib monotherapy in patients with follicular lymphoma and small lymphocytic lymphoma after two prior systemic therapies
Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 delta, in patients with relapsed or refractory non-Hodgkin lymphoma. Blood. 2010;116(21):741.
Horwitz SM, Flinn IW, Patel MR, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma. J Clin Oncol. 2013;31(suppl):8518.
Barnes JA, Jacobsen E, Feng Y, Freedman A, Hochberg EP, LaCasce AS, et al. Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma. Haematologica. 2013;98(4):615–9.
Johnston PB, Laplant BR, McPhail ED, Habermann TM, Inwards DJ, Micallef IN, et al. Everolimus plus RCHOP-21 is safe and highly effective for new untreated diffuse large B-cell lymphoma (DLBCL): results of the phase I trial NCCTG1085 (alliance). Blood. 2015;126(23):813.
Karmali R, Dalovisio A, Borgia JA, Venugopal P, Kim BW, Grant-Szymanski K, et al. All in the family: clueing into the link between metabolic syndrome and hematologic malignancies. Blood Rev. 2015;29(2):71–80.
Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, et al. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. 2012;3:e275.
Zhang LH, Kosek J, Wang M, Heise C, Schafer PH, Chopra R. Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br J Haematol. 2013;160(4):487–502.
Yang Y, Shaffer 3rd AL, Emre NC, Ceribelli M, Zhang M, Wright G, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723–37.
Czuczman MS, Davies A, Linton KM, Wagner-Johnston N, Gascoyne RD, Eberhard DA, et al. A phase 2/3 multicenter, randomized study comparing the efficacy and safety of lenalidomide versus investigator’s choice in relapsed/refractory DLBCL. Blood. 2014;124(21):628.
Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105(36):13520–5.
Beguelin 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(5):677–92.
Beguelin WTM, Hatzi K, et al. EZH2 and BCL6 cooperate to create the germinal center B-cell phenotype and induce lymphomas through formation and repression of bivalent chromatin domains. Blood. 2013;122(21):1.
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.
Berg T, Thoene S, Yap D, Wee T, Schoeler N, Rosten P, et al. A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis. Blood. 2014;123(25):3914–24.
Stimson L, Wood V, Khan O, Fotheringham S, La Thangue NB. HDAC inhibitor-based therapies and haematological malignancy. Ann Oncol. 2009;20(8):1293–302.
Crump M. Treatment of relapsed or refractory non-hodgkin lymphoma with the oral isotype selective histone deacetylase inhibitor MGCD0103: interim results from a phase II study. J Clin Oncol. 2008;26(suppl):8528.
Crump M, Coiffier B, Jacobsen ED, Sun L, Ricker JL, Xie H, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol. 2008;19(5):964–9.
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.
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13(4):842–54.
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.
Bradley WD, Arora S, Busby J, Balasubramanian S, Gehling VS, Nasveschuk CG, et al. EZH2 inhibitor efficacy in non-Hodgkin’s lymphoma does not require suppression of H3K27 monomethylation. Chem Biol. 2014;21(11):1463–75.
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.
Rossille D, Gressier M, Damotte D, Maucort-Boulch D, Pangault C, Semana G, 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.
•• Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31(33):4199–206. This phase II trial was the first to demonstrate clinical activity of PD-1 blockade in DLBCL. Patients were treated with pidilizumab after autologous transplantation with a 51% response rate achieved in patients with measurable disease post transplant
Guillaume T, Rubinstein DB, Symann M. Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood. 1998;92(5):1471–90.
Nicolae A, Pittaluga S, Abdullah S, Steinberg SM, Pham TA, Davies-Hill T, et al. EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood. 2015;126(7):863–72.
Iqbal J, Sanger WG, Horsman DE, Rosenwald A, Pickering DL, Dave B, et al. BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. Am J Pathol. 2004;165(1):159–66.
Iqbal J, Meyer PN, Smith LM, Johnson NA, Vose JM, Greiner TC, et al. BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. Clin Cancer Res. 2011;17(24):7785–95.
Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121(20):4021–31. quiz 250
Davids MSSJ, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol. 2014;32:5s(suppl):8522.
Li L, Pongtornpipat P, Tiutan T, Kendrick SL, Park S, Persky DO, et al. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia. 29(8):1702–12.
Ferrajoli A, Faderl S, Ravandi F, Estrov Z. The JAK-STAT pathway: a therapeutic target in hematological malignancies. Curr Cancer Drug Targets. 2006;6(8):671–9.
Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, et al. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009;15(2):114–23.
Alvarez JV, Frank DA. Genome-wide analysis of STAT target genes: elucidating the mechanism of STAT-mediated oncogenesis. Cancer Biol Ther. 2004;3(11):1045–50.
Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015;7(314)
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.
Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.
Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, 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.
Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell. 2012;22(4):547–60.
Mulas MF, Abete C, Pulisci D, Pani A, Massidda B, Dessi S, et al. Cholesterol esters as growth regulators of lymphocytic leukaemia cells. Cell Prolif. 2011;44(4):360–71.
Yang S, Damiano MG, Zhang H, Tripathy S, Luthi AJ, Rink JS, et al. Biomimetic, synthetic HDL nanostructures for lymphoma. Proc Natl Acad Sci U S A. 2013;110(7):2511–6.
Camicia R, Winkler HC, Hassa PO. Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review. Mol Cancer. 2015;14:207.
Alvarado Y, Giles FJ, Swords RT. The PIM kinases in hematological cancers. Expert Rev Hematol. 2012;5(1):81–96.
Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669–74.
Pham LV, Fu L, Tamayo AT, Bueso-Ramos C, Drakos E, Vega F, et al. Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-kappaB-inducing kinase while activating both canonical and alternative nuclear factor-kappaB pathways. Blood. 2011;117(1):200–10.
Han SS, Yun H, Son DJ, Tompkins VS, Peng L, Chung ST, et al. NF-kappaB/STAT3/PI3K signaling crosstalk in iMyc E mu B lymphoma. Mol Cancer. 2010;9:97.
Dasmahapatra G, Patel H, Dent P, Fisher RI, Friedberg J, Grant S. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol. 2013;161(1):43–56.
Ceribelli M, Kelly PN, Shaffer AL, Wright GW, Xiao W, Yang Y, et al. Blockade of oncogenic IΰB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors. Proc Natl Acad Sci. 2014;111(31):11365–70.
Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci U S A. 2014;111(6):2349–54.
Melani C, Roschewski M. Molecular monitoring of cell-free circulating tumor DNA in non-Hodgkin lymphoma. Oncology (Williston Park). 2016;30(8)
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(5):541–9.
• Kurtz DM, Green MR, Bratman SV, Scherer F, Liu CL, Kunder CA, et al. Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood. 2015;125(24):3679–87. This study investigated the utility of immunoglobulin high-throughput sequencing (Ig-HTS) for the detection of molecular disease in plasma as circulating tumor DNA, and peripheral blood as circulating tumor cells, for disease surveillance comparing it to PET/CT as a standard modality. It was demonstrated that circulating tumor DNA may be useful in detection of early relapse
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Reem Karmali has received compensation from Celgene for serving on speakers’ bureaus and from Pharmacyclics and Seattle Genetics for service as a consultant.
Leo I. Gordon declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Lymphoma
Rights and permissions
About this article
Cite this article
Karmali, R., Gordon, L.I. Molecular Subtyping in Diffuse Large B Cell Lymphoma: Closer to an Approach of Precision Therapy. Curr. Treat. Options in Oncol. 18, 11 (2017). https://doi.org/10.1007/s11864-017-0449-1
Published:
DOI: https://doi.org/10.1007/s11864-017-0449-1