Follicular lymphoma: the diminishing role of chemotherapy

Abstract

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, accounting for 70% of cases in Western countries. Despite this unique name, FL is an extremely heterogeneous disease, both clinically and biologically. The basis of FL heterogeneity lies in the different biological pathways which can be activated, because of the variety of gene mutations that can occur. Today, there is a growing interest in the knowledge of these activated pathways, which is also testified by the presence of a new model that incorporates FL mutations to define patient’s prognosis (m7-FLIPI). These evaluations are also appealing because of the recent possibility of using “targeted therapies”. Targeted therapies are new tools, currently applicable in the setting of relapse/refractory (R/R) disease, where we can find a great variety of “chemo-free” combinations. As in other hematologic malignancies, “cellular therapy” enriches FL drug scenario, including T-cell dependent bispecific antibodies and chimeric antigen receptor (CAR) T-cell. Since FL heterogeneity is the basis of the difference in therapeutic efficacy and disease course among patients, the hope for the future is to understand FL biology more deeply, to better comprehend how to obtain more representative samples and pre-treatment prognostic information in order to individualize the treatment strategy as early as frontline therapy.

Keywords

Follicular lymphoma / POD24 / target therapies / chemo-immunotherapy / biological heterogeneity

References

[1] Swerdlow SH,Pileri SA.The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood2016;127:2375-90 PMCID:PMC4874220

[2] Junlén HR,Kimby E.Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry study.Leukemia2015;29:668-76

[3] Ardeshna KM,Smith P.Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial.Lancet Oncol2014;15:424-35

[4] Ott G,Lohr A.Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.Blood2002;99:3806-12

[5] Bosga-Bouwer AG,Boonstra R.Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive.Blood2003;101:1149-54

[6] Loeffler M,Haake A.HaematoSys-ProjectGenomic and epigenomic co-evolution in follicular lymphomas.Leukemia2015;29:456-63

[7] Sarkozy C,Carlton VE.The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma.Oncotarget2017;8:8765-74 PMCID:PMC5352439

[8] Tsujimoto Y,Jaffe E.Involvement of the bcl-2 gene in human follicular lymphoma.Science1985;228:1440-3

[9] Limpens J,Vos C.Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals.Blood1995;85:2528-36.

[10] Smith KG,O’Reilly LA,Strasser A.bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells.J Exp Med2000;191:475-84 PMCID:PMC2195819

[11] Araf S,Korfi K.Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma.Leukemia2018;32:1261-5 PMCID:PMC5940637

[12] Mamessier E,Eberle FC.Early lesions of follicular lymphoma: a genetic perspective.Haematologica2014;99:481-8 PMCID:PMC3943311

[13] Okosun J,Wang J.Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.Nat Genet2014;46:176-81 PMCID:PMC3907271

[14] Morin RD,Mungall AJ.Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.Nature2011;476:298-303 PMCID:PMC3210554

[15] Kridel R,Mottok A.Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.PLoS Med2016;13:e1002197 PMCID:PMC5154502

[16] Zhang J,Hussein S.Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.Nat Med2015;21:1190-8 PMCID:PMC5145002

[17] Ortega-Molina A,Canela A.The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.Nat Med2015;21:1199-208 PMCID:PMC4676270

[18] Zhang J,Wells VA.The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.Cancer Discov2017;7:322-37 PMCID:PMC5386396

[19] Caganova M,Varano G.Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis.J Clin Invest2013;123:5009-22 PMCID:PMC3859423

[20] Mondello P,Teater M.Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma.Cancer Discov2020;10:440-59 PMCID:PMC7275250

[21] Sugimoto T.Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis.J Clin Exp Hematop2016;56:1-19 PMCID:PMC6247780

[22] Delfau-Larue MH,Dupuis J.Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma.Blood Adv2018;2:807-16 PMCID:PMC5894260

[23] Pastore A,Kridel R.Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.Lancet Oncol2015;16:1111-22

[24] Solal-Céligny P,Colombat P.Follicular lymphoma international prognostic index.Blood2004;104:1258-65

[25] Federico M,Marcheselli L.Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.J Clin Oncol2009;27:4555-62

[26] Batlevi CL,Alperovich A.Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups.Blood Cancer J2020;10:74 PMCID:PMC7366724

[27] Huet S,Jais J.A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts.Lancet Oncol2018;19:549-61 PMCID:PMC5882539

[28] Casulo C,Dawson KL.Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study.J Clin Oncol2015;33:2516-22 PMCID:PMC4879714

[29] Sortais C,Tessoulin B.Progression of disease within 2 years (POD24) is a clinically relevant endpoint to identify high-risk follicular lymphoma patients in real life.Ann Hematol2020;99:1595-604

[30] Jurinovic V,Pfreundschuh M.Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group.Biol Blood Marrow Transplant2018;24:1172-9

[31] Casulo C,Ahn KW.Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis.Biol Blood Marrow Transplant2018;24:1163-71 PMCID:PMC5993598

[32] Casulo C,Le-Rademacher J.Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials.Blood2022;139:1684-93

[33] Maurer MJ,Ghesquières H.Early event status informs subsequent outcome in newly diagnosed follicular lymphoma.Am J Hematol2016;91:1096-101 PMCID:PMC5073042

[34] Trotman J,Belada D.Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial.Lancet Oncol2018;19:1530-42

[35] Trotman J,Lamy T.Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants.J Clin Oncol2011;29:3194-200

[36] Meignan M,Versari A.Baseline Metabolic Tumor Volume Predicts Outcome in High-Tumor-Burden Follicular Lymphoma: A Pooled Analysis of Three Multicenter Studies.J Clin Oncol2016;34:3618-26

[37] Guadagnolo BA,Neuberg D.Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy.Int J Radiat Oncol Biol Phys2006;64:928-34

[38] Cencini E,Rigacci L.Radiotherapy plus rituximab as first-line regimen for localized follicular lymphoma.Leuk Lymphoma2018;59:1420-6

[39] Brice P,Lepage E.Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte.J Clin Oncol1997;15:1110-7

[40] Colombat P,Brousse N.Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation.Blood2001;97:101-6

[41] Rummel MJ,Maschmeyer G.Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet2013;381:1203-10

[42] Flinn IW,Kahl BS.Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study.Blood2014;123:2944-52 PMCID:PMC4260975

[43] Flinn IW,Kahl B.First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study.J Clin Oncol2019;37:984-91 PMCID:PMC6494265

[44] Moccia AA,Schär S.Prolonged rituximab maintenance in follicular lymphoma patients: long-term results of the SAKK 35/03 randomized trial.Blood Adv2020;4:5951-7 PMCID:PMC7724909

[45] Hiddemann W,Canales MA.Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety.J Clin Oncol2018;36:2395-404

[46] Leonard JP,Ketas JC.Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma.J Clin Oncol2003;21:3051-9

[47] Leonard JP,Ketas J.Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin's lymphoma.J Clin Oncol2005;23:5044-51

[48] Leonard JP,Emmanouilides C.Durable complete responses from therapy with combined epratuzumab and rituximab: final results from an international multicenter, phase 2 study in recurrent, indolent, non-Hodgkin lymphoma.Cancer2008;113:2714-23

[49] Grant BW,Johnson JL.A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701.Cancer2013;119:3797-804 PMCID:PMC3828050

[50] Morschhauser F,Feugier P.RELEVANCE Trial InvestigatorsRituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma.N Engl J Med2018;379:934-47

[51] Bachy E,Feugier P.Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study.Blood2022;139:2338-46

[52] Luminari S,Galimberti S.Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 StudyJ Clin Oncol 2022;40:729-39.

[53] Dreyling M,Rule S.Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosistreatment and follow-upAnn Oncol 2021;32:298-308.

[54] Montoto S,Dreyling M.Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party.Haematologica2013;98:1014-21 PMCID:PMC3696603

[55] Kahl BS,Leonard JP.Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study.Cancer2010;116:106-14 PMCID:PMC2916680

[56] Rueda A,Casanova M.Efficacy of the combination of rituximab-bendamustine as a second-line treatment in patients with follicular lymphoma who progress after immunochemotherapy: a phase II trial of the Spanish Lymphoma Oncology Group.Leuk Lymphoma2019;60:1576-9

[57] Sehn LH,Offner FC.Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study.J Clin Oncol2015;33:3467-74 PMCID:PMC5087315

[58] Radford J,Cartron G.Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000).Blood2013;122:1137-43

[59] Sehn LH,Mayer J.Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial.Lancet Oncol2016;17:1081-93

[60] Cheson BD,Mayer J.Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study.J Clin Oncol2018;36:2259-66

[61] Czuczman MS,Witzig TE.Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma.J Clin Oncol2005;23:4390-8

[62] Leonard JP,Younes A.A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma.Ann Oncol2007;18:1216-23

[63] Czuczman MS,Jung S.Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness.Ann Oncol2012;23:2356-62 PMCID:PMC5808680

[64] Lansigan F,Pitcher B.The prognostic significance of PFS24 in follicular lymphoma following firstline immunotherapy: A combined analysis of 3 CALGB trials.Cancer Med2019;8:165-73 PMCID:PMC6346218

[65] Jurczak W,Gaidano G.Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.Ann Oncol2018;29:1266-72 PMCID:PMC5961010

[66] Witzig TE,Gordon LI.Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan.Cancer2007;109:1804-10

[67] Hernandez-Ilizaliturri FJ,Holkova B,Czuczman MS.Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model.Clin Cancer Res2005;11:5984-92

[68] Chong EA,Aqui NA.Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas.Clin Cancer Res2015;21:1835-42

[69] Leonard JP,Johnson J.Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance).J Clin Oncol2015;33:3635-40 PMCID:PMC4622102

[70] Leonard JP,Izutsu K.AUGMENT Trial InvestigatorsAUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma.J Clin Oncol2019;37:1188-99 PMCID:PMC7035866

[71] Morschhauser F,Chaidos A.Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.Lancet Oncol2020;21:1433-42 PMCID:PMC8427481

[72] Gopal AK,de Vos S.PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.N Engl J Med2014;370:1008-18 PMCID:PMC4039496

[73] Salles G,de Vos S.Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: a subgroup analysis of a phase 2 study.Haematologica2017;102:e156-9 PMCID:PMC5395130

[74] Gopal AK,Flowers CR.Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy.Blood2017;129:3037-9

[75] Cheah CY.Idelalisib in the management of lymphoma.Blood2016;128:331-6 PMCID:PMC5161010

[76] Cuneo A,Danesi R.Management of adverse events associated with idelalisib treatment in chronic lymphocytic leukemia and follicular lymphoma: A multidisciplinary position paper.Hematol Oncol2019;37:3-14 PMCID:PMC6585802

[77] Flinn IW,Ardeshna KM.DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.J Clin Oncol2019;37:912-22

[78] Dreyling M,Mollica L.Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma.J Clin Oncol2017;35:3898-905

[79] Fowler NH,Jurczak W.Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma.J Clin Oncol2021;39:1609-18 PMCID:PMC8148421

[80] Forero-Torres A,Yacoub A.Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies.Blood2019;133:1742-52 PMCID:PMC6543513

[81] Proudman D,Gupta D,Yang J.A Matching-Adjusted Indirect Comparison of Single-Arm Trials in Patients with Relapsed or Refractory Follicular Lymphoma Who Received at Least Two Prior Systemic Treatments: Tazemetostat was Associated with a Lower Risk for Safety Outcomes Versus the PI3-Kinase Inhibitors Idelalisib, Duvelisib, Copanlisib, and Umbralisib.Adv Ther2022;39:1678-96 PMCID:PMC8989805

[82] Gopal AK,Fowler NH.Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study.J Clin Oncol2018;36:2405-12

[83] Bartlett NL,LaPlant BR.Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial.Blood2018;131:182-90 PMCID:PMC5757691

[84] Tam CS,Nicol A.Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma.Blood Adv2020;4:4802-11 PMCID:PMC7556127

[85] Mato AR,Jurczak W.Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.Lancet2021;397:892-901

[86] National Comprehensive Cancer Network (NCCN) guidelines. Version 5.2021, 09/22/21

[87] Seymour JF,Eichhorst B.Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia.N Engl J Med2018;378:1107-20

[88] Eyre TA,Fox CP.The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.Br J Haematol2020;188:918-23 PMCID:PMC7528953

[89] Tam CS,Pott C.Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.N Engl J Med2018;378:1211-23

[90] Davids MS,Kenkre VP.Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study.Clin Cancer Res2021;27:4690-5

[91] Serrat N,Matas-Céspedes A.PI3Kδ inhibition reshapes follicular lymphoma-immune microenvironment cross talk and unleashes the activity of venetoclax.Blood Adv2020;4:4217-31 PMCID:PMC7479943

[92] Zinzani PL,Yuen SLS.Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma.Blood2020;136:2628-37 PMCID:PMC7735159

[93] Li D,Yu SF.DCDT2980S, an anti-CD22-monomethyl auristatin E antibody-drug conjugate, is a potential treatment for non-Hodgkin lymphoma.Mol Cancer Ther2013;12:1255-65

[94] Palanca-wessels MCA,Salles G.Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.Lancet Oncol2015;16:704-15

[95] Morschhauser F,Advani R.Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS).Lancet Haematol2019;6:e254-65

[96] 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.Lancet Oncol2021;22:790-800

[97] Hamadani M,Carlo-Stella C.Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma.Blood2021;137:2634-45 PMCID:PMC8138546

[98] Jacobson C,Sehgal AR.Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL).Blood2020;136:40-1

[99] Hirayama VA,Hay KA.High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy.Blood2019;134:636-40 PMCID:PMC6695558

[100] Schuster SJ.Bispecific antibodies for the treatment of lymphomas: Promises and challenges.Hematol Oncol2021;39 Suppl 1:113-6

[101] 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

[102] Budde LE,Sehn LH.Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study.J Clin Oncol2022;40:481-91 PMCID:PMC8824395

[103] Bartlett NL,Budde LE.Subcutaneous (SC) Administration of Mosunetuzumab with Cycle 1 Step-up Dosing Is Tolerable and Active in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphomas (R/R B-NHL): Initial Results from a Phase I/II Study.Blood2021;138:3573-3573

[104] Hutchings M,Clausen MR.Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study.Lancet2021;398:1157-69

[105] Hutchings M,Iacoboni G.Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial.J Clin Oncol2021;39:1959-70 PMCID:PMC8210975

[106] 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

[107] Budde LE,AJ . Mozunetuzumab plus polatuzumab vedotin has promising efficacy and a favorable safety profile in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: updated results from a phase Ib/II study. Abstract #533. Presented at the 2021 ASH Annual Meeting, December 12, 2021.