Diffuse large B‐cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment

Diffuse large B‐cell lymphoma (DLBCL) is the most common type of aggressive non‐Hodgkin lymphoma originating from the germinal center, and it represents a heterogeneous group of diseases with variable outcomes that are differentially characterized by clinical features, cell of origin (COO), molecular features, and most recently, frequently recurring mutations.

[1]  J. Vose,et al.  Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience , 2018, Blood.

[2]  N. Gray,et al.  BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism. , 2018, Blood.

[3]  R. Advani,et al.  The World Health Organization Classification of Lymphoid Neoplasms , 2013 .

[4]  I. Flinn,et al.  CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial , 2017, Haematologica.

[5]  J. Bertino,et al.  ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in “double hit” lymphoma cells , 2015, Leukemia & lymphoma.

[6]  M. Shipp,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. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Juliet Investigators.  Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma , 2019 .

[8]  G. Salles,et al.  Phase II study of single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). , 2017 .

[9]  I. Lossos,et al.  Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Peter Martin,et al.  Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  F. Hernandez-Ilizaliturri,et al.  A multi-institutional outcomes analysis of patients with relapsed or refractory DLBCL treated with ibrutinib. , 2017, Blood.

[12]  N. Schmitz,et al.  Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study , 2016, Bone Marrow Transplantation.

[13]  J. Vose,et al.  Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Philip M Kluin,et al.  Double-hit B-cell lymphomas. , 2011, Blood.

[15]  S. Pileri,et al.  Long‐term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B‐cell lymphoma patients , 2013, Hematological oncology.

[16]  A. Rosenwald,et al.  The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  J. Cerhan,et al.  Inferior survival in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is not associated with MYC/IG gene rearrangements , 2018, Haematologica.

[18]  J. Friedberg,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. , 2014, The Lancet. Oncology.

[19]  A. Rosenwald,et al.  Prognostic Significance of MYC Single, Double, Triple Hit and MYC-Translocation Partner Status in Diffuse Large B-Cell Lymphoma - a Study By the Lunenburg Lymphoma Biomarker Consortium (LLBC) , 2018, Blood.

[20]  R. Gascoyne,et al.  MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. , 2009, Blood.

[21]  W. Chan,et al.  Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  E. Giné,et al.  Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. , 2011, Blood.

[23]  Scott E. Smith,et al.  Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303 , 2016 .

[24]  H. Handa,et al.  Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN , 2013, British journal of haematology.

[25]  Roland Schmitz,et al.  Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma , 2015, Nature Medicine.

[26]  G. Salles,et al.  Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind , 2018, Blood.

[27]  A. Rosenwald,et al.  Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  S. Karasawa,et al.  Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide , 2012, Leukemia.

[29]  J. Burke,et al.  Obinutuzumab or Rituximab Plus CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma: Final Results from an Open-Label, Randomized Phase 3 Study (GOYA) , 2016 .

[30]  S. Barrans,et al.  DIFFERENTIAL EFFICACY OF BORTEZOMIB IN SUBTYPES OF DIFFUSE LARGE B‐CELL LYMPHOMA (DLBL): a PROSPECTIVE RANDOMISED STUDY STRATIFIED BY TRANSCRIPTOME PROFILING: REMODL‐B , 2017 .

[31]  R. Levy,et al.  Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma , 2017, The New England journal of medicine.

[32]  S. Karasawa,et al.  Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide , 2012, Leukemia.

[33]  M. Takei,et al.  Clinical significance of co-expression of MYC and BCL2 protein in aggressive B-cell lymphomas treated with a second line immunochemotherapy , 2016, Leukemia & lymphoma.

[34]  J. Leonard,et al.  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. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  N. Nakamura,et al.  Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations , 2009, Haematologica.

[36]  A. Fattaey,et al.  Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers , 2016, Molecular Cancer Therapeutics.

[37]  Zheng Zhou,et al.  Diffuse large B‐cell lymphoma with primary treatment failure: Ultra‐high risk features and benchmarking for experimental therapies , 2017, American journal of hematology.

[38]  N. Schmitz,et al.  Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  L. Staudt,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[40]  Roland Schmitz,et al.  Genetics and Pathogenesis of Diffuse Large B‐Cell Lymphoma , 2018, The New England journal of medicine.

[41]  Ryan D. Morin,et al.  Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  Matthew J. Frigault,et al.  Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance and Toxicity , 2018, Blood.

[43]  M. Shipp,et al.  A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039) , 2016 .

[44]  W. Wilson,et al.  Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype , 2014, Clinical Cancer Research.

[45]  A. Jemal,et al.  Cancer statistics, 2019 , 2019, CA: a cancer journal for clinicians.

[46]  J. Vose,et al.  Conditioning regimens for allotransplants for diffuse large B-cell lymphoma: myeloablative or reduced intensity? , 2012, Blood.

[47]  M. Esteller,et al.  Bromodomain inhibitors and cancer therapy: From structures to applications , 2016, Epigenetics.

[48]  L. Staudt,et al.  Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  C. Copie-Bergman,et al.  MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. , 2015, Blood.

[50]  W. Chan,et al.  Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma. , 2017, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[51]  A. Rosenwald,et al.  High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. , 2018, Blood.

[52]  A. Hagenbeek,et al.  Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. , 1995, The New England journal of medicine.

[53]  T. Kipps,et al.  Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  Hong Zhang,et al.  Inhibition of Bromodomain Proteins for the Treatment of Human Diffuse Large B-cell Lymphoma , 2014, Clinical Cancer Research.

[55]  Michael L. Wang,et al.  Double hit lymphoma: the MD Anderson Cancer Center clinical experience , 2014, British journal of haematology.

[56]  Outcome of Patients with Double-Expressor Lymphomas (DELs) Treated with R-CHOP or R-EPOCH , 2016 .

[57]  A. Olshen,et al.  Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL. , 2005, Blood.

[58]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[59]  N. Schmitz,et al.  Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study , 2017, Bone Marrow Transplantation.

[60]  R. Gascoyne,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. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  R. Gascoyne,et al.  An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. , 2014, Blood.

[62]  Dirk Hasenclever,et al.  Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  S. Barrans,et al.  Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  J. Vose,et al.  An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[65]  R. Gascoyne,et al.  Allogeneic haematopoietic stem‐cell transplantation for relapsed and refractory aggressive histology non‐Hodgkin lymphoma * , 2005, British journal of haematology.

[66]  C. Buske,et al.  Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[67]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[68]  L. Staudt,et al.  Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  Michael L. Wang,et al.  Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial , 2013, Leukemia.

[70]  David Cunningham,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 , 2013, The Lancet.

[71]  W. Choi,et al.  CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. , 2013, Blood.

[72]  L. Staudt,et al.  Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. , 2009, Blood.

[73]  Scott E. Smith,et al.  Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. , 2014, Blood.

[74]  Stefano Monti,et al.  Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes , 2018, Nature Medicine.

[75]  A. Rosenwald,et al.  MYC diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation , 2012 .

[76]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[77]  S. Lade,et al.  Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy , 2018, International journal of molecular sciences.

[78]  J. Cerhan,et al.  Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. , 2017, Blood.

[79]  A. Zelenetz,et al.  Outcomes of primary refractory diffuse large B‐cell lymphoma (DLBCL) treated with salvage chemotherapy and intention to transplant in the rituximab era , 2017, British journal of haematology.

[80]  L. Staudt,et al.  A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma , 2017, Clinical Cancer Research.

[81]  M. Pfreundschuh,et al.  Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. , 2016, Blood.

[82]  T. Calimeri,et al.  Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. , 2017, The Lancet. Haematology.

[83]  D. Dunson,et al.  Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma , 2017, Cell.

[84]  W. Choi,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. , 2013, Blood.

[85]  High Risk Diffuse Large B Cell Lymphoma: A Comparison of Aggressive Subtypes Treated with Dose Adjusted Chemotherapy-the University of Texas MD Anderson Experience , 2016 .

[86]  M. Millenson,et al.  Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[87]  A. Zelenetz,et al.  A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL. , 2018, Blood.

[88]  Catherine Thieblemont,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. , 2013, The Lancet. Oncology.

[89]  K. Young,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. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[90]  Zheng Zhou,et al.  C‐MYC–positive relapsed and refractory, diffuse large B‐cell lymphoma: Impact of additional “hits” and outcomes with subsequent therapy , 2017, Cancer.

[91]  Michael Hummel,et al.  Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. , 2010, Blood.

[92]  W. Chan,et al.  Cell of origin fails to predict survival in patients with diffuse large B‐cell lymphoma treated with autologous hematopoietic stem cell transplantation , 2012, Hematological oncology.

[93]  J. Friedberg.  Double-hit diffuse large B-cell lymphoma. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[94]  S. Schuster,et al.  Front‐line, dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis , 2015, British journal of haematology.