Diffuse large B-Cell lymphoma: from novel molecular classifications to tailored targeted therapies

Jennifer K. Lue , Grzegorz S. Nowakowski

Journal of Cancer Metastasis and Treatment ›› 2022, Vol. 8 : 11

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Journal of Cancer Metastasis and Treatment ›› 2022, Vol. 8:11 DOI: 10.20517/2394-4722.2021.193
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Diffuse large B-Cell lymphoma: from novel molecular classifications to tailored targeted therapies

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease comprising multiple genetic subtypes that translates and impacts clinical outcomes after standard chemoimmunotherapy. Our initial understanding of the complex biological subtypes of DLBCL began with the identification of cell of origin (COO), and now has evolved to include even more specific subtypes defined by genetic signatures and mutations. These newer classifications lend themselves to the application of precision-based medicine, allowing us to tailor new treatment platforms that target specific oncogenic drivers in order to improve DLBCL outcomes. Essential to this is the development of genetic assays and tools that are reliable and readily available to assist in the application of these molecular classifications to real-world use. In this review, we discuss the history of DLBCL classification systems and their implication on clinical investigation as well as novel therapeutic options in DLBCL.

Keywords

DLBCL / tumor heterogeneity / activated-B-cell / germinal center / molecular targets

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Jennifer K. Lue, Grzegorz S. Nowakowski. Diffuse large B-Cell lymphoma: from novel molecular classifications to tailored targeted therapies. Journal of Cancer Metastasis and Treatment, 2022, 8: 11 DOI:10.20517/2394-4722.2021.193

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References

[1]

Rosenwald A,Chan WC.Lymphoma/Leukemia Molecular Profiling ProjectThe use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.N Engl J Med2002;346:1937-47

[2]

Schmitz R,Huang DW.Genetics and pathogenesis of diffuse large b-cell lymphoma.N Engl J Med2018;378:1396-407 PMCID:PMC6010183

[3]

Chapuy B,Dunford AJ.Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.Nat Med2018;24:679-90 PMCID:PMC6613387

[4]

Wright GW,Phelan JD.A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications.Cancer Cell2020;37:551-568.e14 PMCID:PMC8459709

[5]

Ennishi D,Boyle M.Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma.J Clin Oncol2019;37:190-201 PMCID:PMC6804880

[6]

Song JY,Herrera AF.Double-hit signature with.TP53136:25-6 PMCID:PMC8923151

[7]

Fang JM,Hussong JW,Cubbon AR.CD10 antigen expression correlates with the t(14;18)(q32;q21) major breakpoint region in diffuse large B-cell lymphoma. Mod Pathol 1999;12(3):295-300. (In eng).

[8]

Xu Y,Molberg KH.Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2.Am J Clin Pathol2001;116:183-90

[9]

Harada S,Uehira K.Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5- with CD10+ groups may constitute clinically relevant subtypes.Leukemia1999;13:1441-7

[10]

Uherova P,Schnitzer B,Finn WG.The clinical significance of CD10 antigen expression in diffuse large B-cell lymphoma.Am J Clin Pathol2001;115:582-8

[11]

Alizadeh AA,Davis RE.Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.Nature2000;403:503-11

[12]

Shipp MA,Tamayo P.Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.Nat Med2002;8:68-74

[13]

Wright G,Rosenwald A,Wiestner A.A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma.Proc Natl Acad Sci U S A2003;100:9991-6 PMCID:PMC187912

[14]

Monti S,Kutok JL.Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.Blood2005;105:1851-61

[15]

Hans CP,Greiner TC.Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.Blood2004;103:275-82

[16]

Choi WW,Greiner TC.A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy.Clin Cancer Res2009;15:5494-502 PMCID:PMC7289055

[17]

Meyer PN,Greiner TC.Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab.J Clin Oncol2011;29:200-7 PMCID:PMC3058275

[18]

Gutiérrez-García G,Climent F.Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB)Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.Blood2011;117:4836-43

[19]

Scott DW,Williams PM.Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue.Blood2014;123:1214-7 PMCID:PMC3931191

[20]

Yoon N,Yong Yoo H,Seog Kim W.Cell-of-origin of diffuse large B-cell lymphomas determined by the Lymph2Cx assay: better prognostic indicator than Hans algorithm.Oncotarget2017;8:22014-22 PMCID:PMC5400642

[21]

Lenz G,Dave SS.Lymphoma/Leukemia Molecular Profiling ProjectStromal gene signatures in large-B-cell lymphomas.N Engl J Med2008;359:2313-23

[22]

Scott DW,Ennishi D.Prognostic significance of diffuse large B-Cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies.J Clin Oncol2015;33:2848-56 PMCID:PMC4554747

[23]

Vitolo U,Gascoyne R.on behalf of the ROBUST study investigatorsROBUST: first report of phase III randomized study of lenalidomide/R-CHOP (R 2 -CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma.Hematol Oncol2019;37:36-7

[24]

Nowakowski GS,Witzig TE.ROBUST: lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma.Future Oncol2016;12:1553-63 PMCID:PMC5551933

[25]

Maurer MJ,Habermann TM.Time from diagnosis to initiation of treatment of DLBCL and implication for potential selection bias in clinical trials. blood 2016;128:3034.

[26]

Reddy A,Davis NS.Genetic and functional drivers of diffuse large B cell lymphoma.Cell2017;171:481-494.e15 PMCID:PMC5659841

[27]

Johnson NA,Ludkovski O.Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival.Blood2009;114:2273-9 PMCID:PMC2745846

[28]

Savage KJ,Ben-Neriah S.MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy.Blood2009;114:3533-7

[29]

Green TM,de Stricker K,Young KH.High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma.Am J Surg Pathol2012;36:612-9

[30]

Wan JCM,Garcia-Corbacho J.Liquid biopsies come of age: towards implementation of circulating tumour DNA.Nat Rev Cancer2017;17:223-38

[31]

Hiemcke-Jiwa LS,Radersma-van Loon JH.The use of droplet digital PCR in liquid biopsies: a highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid.Hematol Oncol2018;36:429-35

[32]

Yamagishi Y,Nakano Y.Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma.Cancer Sci2021;112:4702-10 PMCID:PMC8586690

[33]

Roschewski M,Pittaluga S.Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study.The Lancet Oncology2015;16:541-9 PMCID:PMC4460610

[34]

Kurtz DM,Bratman SV.Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing.Blood2015;125:3679-87 PMCID:PMC4463733

[35]

Newman AM,Klass DM.Integrated digital error suppression for improved detection of circulating tumor DNA.Nat Biotechnol2016;34:547-55 PMCID:PMC4907374

[36]

Scherer F,Newman AM.Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA.Sci Transl Med2016;8:364ra155 PMCID:PMC5490494

[37]

Kurtz DM,Jin MC.Circulating tumor DNA measurements as early outcome predictors in diffuse large B-Cell lymphoma.J Clin Oncol2018;36:2845-53 PMCID:PMC6161832

[38]

Kurtz DM,Co Ting Keh L.Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.Nat Biotechnol2021;39:1537-47 PMCID:PMC8678141

[39]

Récher C,Haioun C.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.Lancet2011;378:1858-67

[40]

Delarue R,Mounier N.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.The Lancet Oncology2013;14:525-33

[41]

Lugtenburg EJ,van der Holt B.Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: results from a randomized HOVON-Nordic lymphoma group phase III study.JCO2019;37:7507-7507

[42]

Bartlett NL,Jung SH.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 Oncol2019;37:1790-9 PMCID:PMC6774813

[43]

Vitolo U,Belada D.Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-Cell lymphoma.J Clin Oncol2017;35:3529-37

[44]

Crump M,Fayad L.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 Oncol2016;34:2484-92

[45]

Thieblemont C,Gomes da Silva M.Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-Cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.J Clin Oncol2017;35:2473-81

[46]

Witzig TE,Rigacci L.Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial.Ann Oncol2018;29:707-14

[47]

Leonard JP,Reeves JA.Randomized phase ii study of r-chop with or without bortezomib in previously untreated patients with non-germinal center B-Cell-Like diffuse large B-Cell lymphoma.J Clin Oncol2017;35:3538-46

[48]

Davies A,Barrans S.Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial.The Lancet Oncology2019;20:649-62 PMCID:PMC6494978

[49]

Younes A,Johnson P.PHOENIX investigatorsRandomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-Cell diffuse large B-Cell lymphoma.J Clin Oncol2019;37:1285-95 PMCID:PMC6553835

[50]

Nowakowski G,Scott D.Addition of lenalidomide to r-chop (R2chop) improves outcomes in newly diagnosed diffuse large B-Cell lymphoma (DLBCL): first report of ecog-acrin1412 a randomized phase 2 us intergroup study of R2chop vs R-chop Hematol Oncol 2019;37:37-8.

[51]

Tilly H,Sehn LH.Polatuzumab vedotin in previously untreated diffuse large B-Cell lymphoma.N Engl J Med2022;386:351-63

[52]

Philip T,Hagenbeek A.Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma.N Engl J Med1995;333:1540-5

[53]

Gisselbrecht C,Mounier N.Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era.J Clin Oncol2010;28:4184-90 PMCID:PMC3664033

[54]

Schuster SJ,Tam CS.JULIET InvestigatorsTisagenlecleucel in adult relapsed or refractory diffuse large B-Cell lymphoma.N Engl J Med2019;380:45-56

[55]

Neelapu SS,Bartlett NL.Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-Cell lymphoma.N Engl J Med2017;377:2531-44 PMCID:PMC5882485

[56]

Locke FL,Jacobson CA.Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.The Lancet Oncology2019;20:31-42 PMCID:PMC6733402

[57]

Schuster SJ,Tam CS.Long-term follow-up of tisagenlecleucel in adult patients with relapsed or refractory diffuse large B-Cell lymphoma: updated analysis of juliet study.Biology of Blood and Marrow Transplantation2019;25:S20-1

[58]

Compagno M,Grunn A.Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.Nature2009;459:717-21 PMCID:PMC2973325

[59]

Honma K,Nakagawa M.TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas.Blood2009;114:2467-75

[60]

Rawlings DJ,Moreno-García ME.The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes.Nat Rev Immunol2006;6:799-812

[61]

Davis RE,Lenz G.Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.Nature2010;463:88-92 PMCID:PMC2845535

[62]

Ngo VN,Schmitz R.Oncogenically active MYD88 mutations in human lymphoma.Nature2011;470:115-9 PMCID:PMC5024568

[63]

Hailfinger S,Ngo V.Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma.Proc Natl Acad Sci U S A2009;106:19946-51 PMCID:PMC2785272

[64]

Phelan JD,Webster DE.A multiprotein supercomplex controlling oncogenic signalling in lymphoma.Nature2018;560:387-91 PMCID:PMC6201842

[65]

Lucas PC,Inohara N.Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway.J Biol Chem2001;276:19012-9

[66]

Wilson WH,Schmitz R.Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma.Nat Med2015;21:922-6 PMCID:PMC8372245

[67]

Dyer MJ,Ruan J.Acalabrutinib monotherapy in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).JCO2018;36:7547-7547

[68]

Roschewski M,Hamdy A.PRISM: A Platform Protocol for the Treatment of Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma.Blood2019;134:2869

[69]

Cummin T,Mercer K.Accept: a phase IB/II combination of Acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-Chop) for patients with diffuse large b-cell lymphoma (DLBCL).Hematol Oncol2019;37:71-2

[70]

Johnson PWM,Cumin T.Abstract CT162: ACCEPT: A phase Ib/II combination of acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL). Cancer research 2018;78(13 Supplement):CT162-CT162.DOI: 10.1158/1538-7445.am2018-ct162.

[71]

Lin SC,Wu H.Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling.Nature2010;465:885-90 PMCID:PMC2888693

[72]

Motshwene PG,Grossmann JG.An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4.J Biol Chem2009;284:25404-11 PMCID:PMC2757241

[73]

Beutler B,Georgel P.Genetic analysis of host resistance: toll-like receptor signaling and immunity at large.Annu Rev Immunol2006;24:353-89

[74]

Nowakowski GS,Younes A.Safety, pharmacokinetics and activity of CA-4948, an IRAK4 inhibitor, for treatment of patients with relapsed or refractory hematologic malignancies: results from the phase 1 study.Blood2020;136:44-5

[75]

Nowakowski GS,Joffe E.A multi-center, dose-finding study to assess safety, tolerability, pharmacokinetics and preliminary efficacy of a novel irak4 inhibitor ca-4948 in combination with IBRUTINIB, in patients with relapsed or refractory hematologic malignancies.Blood2020;136:49-50

[76]

Kelleher J,Chen J.Kym-001, a first-in-class oral irak4 protein degrader, induces tumor regression in XENOGRAFT models of myd88-mutant ABC DLBCL alone and in combination with BTK inhibition.Hematol Oncol2019;37:129-129

[77]

Walker D,Klaus C.Ktx-120, a Novel IRAKIMID degrader of IRAK4 and IMID substrates shows preferential activity and induces regressions in MYD88-mutant DLBCL CDX and PDX models.Blood2020;136:41

[78]

Lue JK,Klaus C.Targeting MYD88-Mutant DLBCL with IRAKIMIDS: a comparison to IRAK4 kinase inhibition and evaluation of synergy with rational combinations.Blood2020;136:12

[79]

Fontan L,Kabaleeswaran V.MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.Cancer Cell2012;22:812-24 PMCID:PMC3984478

[80]

Philippar U,Vloemans N.Discovery of a novel, potential first-in-class malt1 protease inhibitor for the treatment of B cell lymphomas.Hematol Oncol2019;37:128-128

[81]

Fontan L,Scott D.Chemically induced degradation of malt1 to treat B-cell lymphomas.Blood2019;134:2073

[82]

Hatcher JM,Fontán L.Peptide-based covalent inhibitors of MALT1 paracaspase.Bioorg Med Chem Lett2019;29:1336-9

[83]

Quancard J,Fung SY.An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.Nat Chem Biol2019;15:304-13

[84]

Lu T,Philippar U.Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease.Bioorg Med Chem Lett2019;29:126743

[85]

Fontán L,Hatcher JM.Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth.J Clin Invest2018;128:4397-412 PMCID:PMC6159983

[86]

first-in-class MALT1 blocker deal.Nat Biotechnol2019;37:112

[87]

Xia M,Teater M.BCL10 gain-of-function mutations aberrantly induce canonical and non-canonical NF-Kb activation and resistance to IBRUTINIB in ABC-DLBCL.Blood2020;136:2-3

[88]

Philippar U,Vloemans N.Abstract 5690: discovery of JNJ-67856633: a novel, first-in-class MALT1 protease inhibitor for the treatment of B cell lymphomas.Cancer research2020;80:5690

[89]

Kiyasu J,Hirata A.Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma.Blood2015;126:2193-201 PMCID:PMC4635115

[90]

Godfrey J,Bao R..PD-L1133:2279-90 PMCID:PMC6911840

[91]

Ansell SM,Johnson P.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 Oncol2019;37:481-9 PMCID:PMC6528729

[92]

Smith SD,Shadman MS.Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy.Br J Haematol2020;189:1119-26

[93]

Nowakowski GS,Greil R.Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R 2 -CHOP in subjects with previously untreated, high-risk DLBCL.JCO2019;37:7520-7520

[94]

Nowakowski GS,Truemper L.And the MEDI4736-DLBCL-001 Trial InvestigatorsPhase II study of durvalumab (anti-PD-L1 antibody) in combination with R-CHOP or lenalidomide plus R-CHOP in previously untreated, high-risk diffuse large B-cell lymphoma.JCO2017;35:TPS7573-TPS7573

[95]

Hawkes EA,Smith C.AvR-CHOP: feasibility study of induction and maintenance AVELUMAB plus R-CHOP in patients with diffuse large B-Cell lymphoma (DLBCL).Blood2019;134:5332

[96]

Klapper W,Zeynalova S.German High-Grade Non-Hodgkin's Lymphoma Study GroupStructural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).Leukemia2008;22:2226-9

[97]

Valera A,Cardesa-Salzmann T.Grup per l’Estudi dels Limfomes de Catalunya i Balears (GELCAB)MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.Haematologica2013;98:1554-62 PMCID:PMC3789460

[98]

Horn H,Becher C.German High-Grade Non-Hodgkin Lymphoma Study GroupMYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma.Blood2013;121:2253-63

[99]

Barrans S,Smith A.Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab.J Clin Oncol2010;28:3360-5

[100]

Oki Y,Lin P.Double hit lymphoma: the MD Anderson Cancer Center clinical experience.Br J Haematol2014;166:891-901

[101]

Petrich AM,Jovanovic B.Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.Blood2014;124:2354-61

[102]

Wang W,Lu X,Medeiros LJ.Triple-hit B-cell Lymphoma with MYC, BCL2, and BCL6 translocations/rearrangements: clinicopathologic features of 11 cases.Am J Surg Pathol2015;39:1132-9

[103]

Hu S,Tzankov A.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.Blood2013;121:4021-31; quiz 4250 PMCID:PMC3709650

[104]

Morin RD,Severson TM.Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.Nat Genet2010;42:181-5 PMCID:PMC2850970

[105]

Bödör C,Wrench D.EZH2 Y641 mutations in follicular lymphoma.Leukemia2011;25:726-9

[106]

Zhang X,Fiskus W.Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.Cancer Cell2012;22:506-23 PMCID:PMC3973134

[107]

Yan J,Tay JL.EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity.Blood2013;121:4512-20

[108]

Arisan S,Palavan-Unsal N,Cakir OO.Increased expression of EZH2, a polycomb group protein, in bladder carcinoma.Urol Int2005;75:252-7

[109]

Velichutina I,Geng H.EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis.Blood2010;116:5247-55 PMCID:PMC3012542

[110]

Love C,Jima D.The genetic landscape of mutations in Burkitt lymphoma.Nat Genet2012;44:1321-5 PMCID:PMC3674561

[111]

Visser HP,Kluin-Nelemans HC.The polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. British journal of haematology 2001;112(4):950-8. (In eng).

[112]

Eckerle S,Döring C.Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma.Leukemia2009;23:2129-38

[113]

Sasaki D,Hasegawa H.Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy.Haematologica2011;96:712-9 PMCID:PMC3084918

[114]

Varambally S,Zhou M.The polycomb group protein EZH2 is involved in progression of prostate cancer.Nature2002;419:624-9

[115]

Wagener N,Pritsch M.Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma.BMC Cancer2010;10:524 PMCID:PMC2958940

[116]

Kleer CG,Varambally S.EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells.Proc Natl Acad Sci U S A2003;100:11606-11 PMCID:PMC208805

[117]

Garapaty-Rao S,Gagnon A.Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth.Chem Biol2013;20:1329-39

[118]

Knutson SK,Minoshima Y.Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma.Mol Cancer Ther2014;13:842-54

[119]

Qi W,Teng L.Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.Proc Natl Acad Sci U S A2012;109:21360-5 PMCID:PMC3535655

[120]

Italiano A,Toulmonde M.Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.The Lancet Oncology2018;19:649-59

[121]

Morschhauser F,Chaidos A.Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.The Lancet Oncology2020;21:1433-42 PMCID:PMC8427481

[122]

Sarkozy C,Dubois S.A LYSA phase IB study of tazemetostat (EPZ-6438) plus R-CHOP in PATIENTS with newly diagnosed diffuse large B-Cell lymphoma (DLBCL) with poor prognosis features.Clin Cancer Res2020;26:3145-53

[123]

Morishima S,Izutsu K.First-in-human study of the EZH1/2 dual Inhibitor valemetostat in relapsed or refractory non-Hodgkin lymphoma (NHL) - updated results focusing on adult T-cell leukemia-lymphoma (ATL).Blood2019;134:4025

[124]

Pasqualucci L,Chiarenza A.Inactivating mutations of acetyltransferase genes in B-cell lymphoma.Nature2011;471:189-95 PMCID:PMC3271441

[125]

Andersen CL,Klausen T,Grønbæk K.Somatic mutations of the CREBBP and EP300 genes affect response to histone deacetylase inhibition in malignant DLBCL clones.Leuk Res Rep2012;2:1-3 PMCID:PMC3850379

[126]

Zaja F,Rossi M.Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fondazione Italiana Linfomi.Leuk Lymphoma2018;59:2904-10

[127]

Younes A,Patel MR.Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.The Lancet Oncology2016;17:622-31 PMCID:PMC5494693

[128]

Oki Y,Flinn I.CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial.Haematologica2017;102:1923-30 PMCID:PMC5664396

[129]

Landsburg DJ,Lugtenburg PJ.A pooled analysis of relapsed/refractory diffuse large B-Cell lymphoma patients treated with the dual PI3K and HDAC inhibitor fimepinostat (CUDC-907), including patients with MYC-Altered Disease.Blood2018;132:4184

[130]

Lovén J,Lin CY.Selective inhibition of tumor oncogenes by disruption of super-enhancers.Cell2013;153:320-34 PMCID:PMC3760967

[131]

Cinar M,Rokhsar S.Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas.Leuk Res2015;39:730-8

[132]

Esteve-Arenys A,Chamorro-Jorganes A.The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma.Oncogene2018;37:1830-44

[133]

Johnson NA,Savage KJ.Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.J Clin Oncol2012;30:3452-9 PMCID:PMC3454768

[134]

Davids MS,Seymour JF.Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma.J Clin Oncol2017;35:826-33 PMCID:PMC5455685

[135]

Zelenetz AD,Mason KD.Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial.Blood2019;133:1964-76 PMCID:PMC6497517

[136]

Rutherford SC,Bartlett NL.Phase I study of the Bcl-2 inhibitor venetoclax with DA-EPOCH-R as initial therapy for aggressive B-cell lymphomas.JCO2020;38:8003-8003

[137]

Coiffier B,Briere J.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med2002;346:235-42

[138]

Sehn LH,Flowers CR.Polatuzumab vedotin in relapsed or refractory diffuse large B-Cell lymphoma.J Clin Oncol2020;38:155-65 PMCID:PMC7032881

[139]

Gritti G,Phillips TJ.Polatuzumab vedotin plus venetoclax with rituximab in relapsed/refractory diffuse large B-Cell lymphoma: primary efficacy analysis of a phase IB/II study.Blood2020;136:45-7

[140]

Salles G,González Barca E.Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study.The Lancet Oncology2020;21:978-88

[141]

Duell J,González-barca E.Subgroup analyses from L-mind, a phase II Study of tafasitamab (MOR208) combined with lenalidomide in patients with relapsed or refractory diffuse large B-Cell lymphoma.Blood2019;134:1582

[142]

Burke JM,Cheson BD.A phase IB, open-label, randomized study to assess safety and preliminary efficacy of tafasitamab (MOR208) or tafasitamab + lenalidomide in addition to R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma: the first-mind trial.Blood2019;134:2877

[143]

Caimi PF,Alderuccio JP.Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial.The Lancet Oncology2021;22:790-800

[144]

Jaiswal S,Pang WW.CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis.Cell2009;138:271-85 PMCID:PMC2775564

[145]

Chao MP,Tang C.Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma.Cell2010;142:699-713 PMCID:PMC2943345

[146]

Advani R,Popplewell L.CD47 blockade by Hu5F9-G4 and rituximab in non-hodgkin’s lymphoma.N Engl J Med2018;379:1711-21 PMCID:PMC8058634

[147]

Schuster SJ,Assouline S.Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (car-t) therapies, and is active in treatment through multiple lines.Blood2019;134:6

[148]

Olszewski AJ,Babu S.Single-agent mosunetuzumab is a Promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B-Cell lymphoma.Blood2020;136:43-5

[149]

Bannerji R,Arnason JE.Odronextamab (REGN1979), a Human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy.Blood2020;136:42-3

[150]

Hutchings M,Clausen MR.Subcutaneous epcoritamab induces complete responses with an encouraging safety profile across relapsed/refractory B-cell non-Hodgkin lymphoma subtypes, including patients with prior car-t therapy: updated dose escalation data.Blood2020;136:45-6

[151]

Bacac M,Herter S.CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies.Clin Cancer Res2018;24:4785-97

[152]

Hutchings M,Bachy E.Glofitamab step-up dosing induces high response rates in patients with hard-to-treat refractory or relapsed non-hodgkin lymphoma.Blood2020;136:46-8

[153]

Zhang J.Preclinical study of a novel tri-specific anti-CD3/CD19/CD20 T cell-engaging antibody as a potentially better treatment for NHL.Blood2020;136:22

[154]

Locke FL,Jacobson CA.All ZUMA-7 investigators and contributing kite membersAxicabtagene ciloleucel as second-line therapy for large B-cell lymphoma.N Engl J Med2022;386:640-54

[155]

Kamdar M,Arnason JE.Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) t cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (Pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the randomized phase 3 transform study.Blood2021;138:91

[156]

Bishop MR,Purtill D.Second-line tisagenlecleucel or standard care in aggressive B-Cell lymphoma.N Engl J Med2022;386:629-39

[157]

Park JH,Gonen M.Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia.N Engl J Med2018;378:449-59 PMCID:PMC6637939

[158]

Shah NN.Mechanisms of resistance to CAR T cell therapy.Nat Rev Clin Oncol2019;16:372-85 PMCID:PMC8214555

[159]

Qin JS,Baturevych A.Antitumor potency of an anti-cd19 chimeric antigen receptor T-Cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib.J Immunother2020;43:107-20 PMCID:PMC7144752

[160]

Otáhal P,Král V.Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells.Oncoimmunology2016;5:e1115940 PMCID:PMC4839314

[161]

Thieblemont C,Allain V.Lenalidomide enhance CAR T-Cells Response in patients with refractory/relapsed large B Cell lymphoma experiencing progression after infusion.Blood2020;136:16-7

[162]

Rupp LJ,Roybal KT.CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells.Sci Rep2017;7:737 PMCID:PMC5428439

[163]

Li S,Zhang X.Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors.Clin Cancer Res2017;23:6982-92

[164]

Hill BT,Xue A,Smith MR.Rapid tumor regression from PD-1 inhibition after anti-CD19 chimeric antigen receptor T-cell therapy in refractory diffuse large B-cell lymphoma.Bone Marrow Transplant2020;55:1184-7 PMCID:PMC7269903

[165]

Funk CR,Chen KZ.PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity.Blood2022;139:523-37 PMCID:PMC8796652

[166]

Shadman M,Redman M.Safety and efficacy of third generation CD20 targeted CAR-T (MB-106) for treatment of relapsed/refractory B-NHL and CLL.Blood2021;138:3872

[167]

Baird JH,Craig J.CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.Blood2021;137:2321-5 PMCID:PMC8085484

[168]

Zah E,Silva-Benedict A,Chen YY.T Cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by Malignant B cells.Cancer Immunol Res2016;4:498-508 PMCID:PMC4933590

[169]

Tong C,Liu Y.Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma.Blood2020;136:1632-44 PMCID:PMC7596761

[170]

Kalakonda N,Cavallo F.Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.The Lancet Haematology2020;7:e511-22

[171]

Pfreundschuh M,Kloess M.German High-Grade Non-Hodgkin's Lymphoma Study GroupTwo-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL.Blood2004;104:634-41

[172]

Khurana A,Nowakowski GS.Impact of organ function-based clinical trial eligibility criteria in patients with diffuse large B-Cell lymphoma: who gets left behind?.J Clin Oncol2021;39:1641-9 PMCID:PMC8274741

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