A Comprehensive Review of Monoclonal Antibodies for the Treatment of Follicular Lymphoma Including Both Approved and Investigational Options
Authors: Moustafa Muhamad 
Published: December 2023

Follicular lymphoma (FL) is the most common type of indolent lymphoma in the Western world, accounting for approximately 30% of lymphoma cases. FL is known for its recurrent nature, necessitating diverse treatment options. The introduction of rituximab, an anti-CD20 antibody, has greatly improved FL outcomes and paved the way for targeted therapies. In this review, we thoroughly explore the structure, mechanism of action, clinical outcomes, and side effects of currently approved monoclonal antibodies (mAb) for FL. Furthermore, we provide insights into ongoing clinical trials and emerging monoclonal antibodies that hold promise for the future of FL treatment. A comprehensive literature search was conducted using various medical databases, including ASH and ASCO publications, as well as PubMed. The clinicaltrials.gov website was used to compile a list of investigational monoclonal antibodies from ongoing clinical trials. The future of antibody-based therapy for follicular lymphoma shows great promise, with a focus on enhancing antibody efficacy, prioritizing optimized combination therapies to address treatment resistance, and evaluating bispecific antibodies as first-line therapies, all while carefully balancing risks and benefits and sequencing treatments appropriately for better disease management. These directions have the potential to establish antibodies as a central component of follicular lymphoma treatment. Article Details How to Cite MOUSTAFA, Muhamad Alhaj. A Comprehensive Review of Monoclonal Antibodies for the Treatment of Follicular Lymphoma Including Both Approved and Investigational Options. Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4745>. Date accessed: 02 dec. 2023. doi: https://doi.org/10.18103/mra.v11i11.4745. ABNT APA BibTeX CBE EndNote - EndNote format (Macintosh & Windows) MLA ProCite - RIS format (Macintosh & Windows) RefWorks Reference Manager - RIS format (Windows only) Turabian Issue Vol 11 No 11 (2023): November Issue, Vol.11, Issue 11 Section Research Articles The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives. References 1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569 2. Cerhan JR. Epidemiology of Follicular Lymphoma. Hematol Oncol Clin North Am. 2020;34(4):631-646. doi:10.1016/j.hoc.2020.02.001 3. Kaseb H, Ali MA, Koshy NV. Follicular Lymphoma. In: StatPearls. StatPearls Publishing; 2023. Accessed April 8, 2023. http://www.ncbi.nlm.nih.gov/books/NBK538206/ 4. Monga N, Nastoupil L, Garside J, et al. Burden of illness of follicular lymphoma and marginal zone lymphoma. Ann Hematol. 2019;98(1):175-183. doi:10.1007/s00277-018-3501-8 5. Mozas P, Sorigué M, López-Guillermo A. Follicular lymphoma: an update on diagnosis, prognosis, and management. Med Clin (Barc). 2021;157(9):440-448. doi:10.1016/j.medcli.2021.03.041 6. Luminari S, Bellei M, Biasoli I, Federico M. Follicular lymphoma - treatment and prognostic factors. Rev Bras Hematol E Hemoter. 2012;34(1):54-59. doi:10.5581/1516-8484.20120015 7. Illidge T, Chan C. How have outcomes for patients with follicular lymphoma changed with the addition of monoclonal antibodies? Leuk Lymphoma. 2008;49(7):1263-1273. doi:10.1080/10428190802090805 8. Steffanoni S, Ghielmini M, Moccia A. Chemotherapy and treatment algorithms for follicular lymphoma: a look at all options. Expert Rev Anticancer Ther. 2015;15(11):1337-1349. doi:10.1586/14737140.2015.1092386 9. Flowers CR, Leonard JP, Nastoupil LJ. Novel immunotherapy approaches to follicular lymphoma. Hematol Am Soc Hematol Educ Program. 2018;2018(1):194-199. doi:10.1182/asheducation-2018.1.194 10. Marofi F, Rahman HS, Achmad MH, et al. A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions. Front Immunol. 2021;12:681984. doi:10.3389/fimmu.2021.681984 11. Bhatt VR, Armitage JO. Autologous and allogeneic hematopoietic stem cell transplantation in follicular lymphoma. Expert Opin Biol Ther. 2016;16(1):57-66. doi:10.1517/14712598.2016.1096341 12. Lin Z, Liu L, Li Z, Xu B. Bispecific antibodies as monotherapy or in combinations for non-hodgkin B-cell lymphoma: latest updates from the American society of hematology 2022 annual meeting. Exp Hematol Oncol. 2023;12(1):41. doi:10.1186/s40164-023-00404-3 13. Coiffier B, Thieblemont C, Van Den Neste E, 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):2040-2045. doi:10.1182/blood-2010-03-276246 14. van Meerten T, Hagenbeek A. Novel antibodies against follicular non-Hodgkin’s lymphoma. Best Pract Res Clin Haematol. 2011;24(2):231-256. doi:10.1016/j.beha.2011.03.002 15. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med. 2017;377(14):1331-1344. doi:10.1056/NEJMoa1614598 16. Johnston PB, Bondly C, Micallef INM. Ibritumomab tiuxetan for non-Hodgkin’s lymphoma. Expert Rev Anticancer Ther. 2006;6(6):861-869. doi:10.1586/14737140.6.6.861 17. Gondran C, Ysebaert L. [Drug approval: Mosunetuzumab - third-line therapy in follicular lymphoma]. Bull Cancer (Paris). 2022;109(11):1105-1106. doi:10.1016/j.bulcan.2022.07.010 18. Allen HC, Sharma P. Histology, Plasma Cells. In: StatPearls. StatPearls Publishing; 2023. Accessed April 11, 2023. http://www.ncbi.nlm.nih.gov/books/NBK556082/ 19. Nelson PN, Reynolds GM, Waldron EE, Ward E, Giannopoulos K, Murray PG. Monoclonal antibodies. Mol Pathol MP. 2000;53(3):111-117. doi:10.1136/mp.53.3.111 20. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495-497. doi:10.1038/256495a0 21. Dunn DL. Monoclonal antibodies for diagnosis and treatment. Arch Surg Chic Ill 1960. 1993;128(11):1274-1280. doi:10.1001/archsurg.1993.01420230102016 22. Posner J, Barrington P, Brier T, Datta-Mannan A. Monoclonal Antibodies: Past, Present and Future. Handb Exp Pharmacol. 2019;260:81-141. doi:10.1007/164_2019_323 23. Di Pauli F, Berger T, Reindl M. Monoclonal antibodies in the treatment of multiple sclerosis. Curr Med Chem. 2009;16(36):4858-4868. doi:10.2174/092986709789909585 24. Lloyd EC, Gandhi TN, Petty LA. Monoclonal Antibodies for COVID-19. JAMA. 2021;325(10):1015. doi:10.1001/jama.2021.1225 25. Kaur N, Goyal A, Sindhu RK. Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer. Anticancer Agents Med Chem. 2020;20(16):1895-1907. doi:10.2174/1871520620666200703191653 26. Yamada T. Therapeutic monoclonal antibodies. Keio J Med. 2011;60(2):37-46. doi:10.2302/kjm.60.37 27. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435-445. 28. Cerny T, Borisch B, Introna M, Johnson P, Rose AL. Mechanism of action of rituximab: Anticancer Drugs. 2002;13:S3-S10. doi:10.1097/00001813-200211002-00002 29. Alas S, Bonavida B. Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res. 2001;61(13):5137-5144. 30. Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95(12):3900-3908. 31. Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am J Hematol. 2022;97(12):1638-1651. doi:10.1002/ajh.26737 32. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(15):1986-1992. doi:10.1200/JCO.2006.06.4618 33. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106(12):3725-3732. doi:10.1182/blood-2005-01-0016 34. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105(4):1417-1423. doi:10.1182/blood-2004-08-3175 35. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(28):4579-4586. doi:10.1200/JCO.2007.13.5376 36. Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008;112(13):4824-4831. doi:10.1182/blood-2008-04-153189 37. Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001;97(1):101-106. doi:10.1182/blood.v97.1.101 38. Ghielmini M, Schmitz SFH, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004;103(12):4416-4423. doi:10.1182/blood-2003-10-3411 39. Witzig TE, Vukov AM, Habermann TM, et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin’s lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(6):1103-1108. doi:10.1200/JCO.2005.12.052 40. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet Lond Engl. 2011;377(9759):42-51. doi:10.1016/S0140-6736(10)62175-7 41. Martinelli G, Schmitz SFH, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(29):4480-4484. doi:10.1200/JCO.2010.28.4786 42. Hanif N, Anwer F. Rituximab. In: StatPearls. StatPearls Publishing; 2023. Accessed April 15, 2023. http://www.ncbi.nlm.nih.gov/books/NBK564374/ 43. Freeman CL, Sehn LH. A tale of two antibodies: obinutuzumab versus rituximab. Br J Haematol. 2018;182(1):29-45. doi:10.1111/bjh.15232 44. Goede V, Klein C, Stilgenbauer S. Obinutuzumab (GA101) for the treatment of chronic lymphocytic leukemia and other B-cell non-hodgkin’s lymphomas: a glycoengineered type II CD20 antibody. Oncol Res Treat. 2015;38(4):185-192. doi:10.1159/000381524 45. Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22):4393-4402. doi:10.1182/blood-2009-06-225979 46. Niederfellner G, Lammens A, Mundigl O, et al. Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies. Blood. 2011;118(2):358-367. doi:10.1182/blood-2010-09-305847 47. Suresh T, Lee LX, Joshi J, Barta SK. New antibody approaches to lymphoma therapy. J Hematol OncolJ Hematol Oncol. 2014;7:58. doi:10.1186/s13045-014-0058-4 48. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013;122(7):1137-1143. doi:10.1182/blood-2013-01-481341 49. Amitai I, Gafter-Gvili A, Shargian-Alon L, Raanani P, Gurion R. Obinutuzumab-related adverse events: A systematic review and meta-analysis. Hematol Oncol. 2021;39(2):215-221. doi:10.1002/hon.2828 50. Riley MB. Ibritumomab tiuxetan. Clin J Oncol Nurs. 2003;7(1):110-112. doi:10.1188/03.CJON.109-112 51. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(16):1977-1983. doi:10.1200/JCO.2012.45.6400 52. Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(15):3262-3269. doi:10.1200/JCO.2002.11.017 53. Rieger K, De Filippi R, Lindén O, et al. 90-yttrium-ibritumomab tiuxetan as first-line treatment for follicular lymphoma: updated efficacy and safety results at an extended median follow-up of 9.6 years. Ann Hematol. 2022;101(4):781-788. doi:10.1007/s00277-022-04781-3 54. Alhaj Moustafa M, Borah BJ, Moriarty JP, et al. Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas. Clin Lymphoma Myeloma Leuk. 2023;23(4):259-265. doi:10.1016/j.clml.2023.01.010 55. Salvaris R, Ong J, Gregory GP. Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas. J Pers Med. 2021;11(5):355. doi:10.3390/jpm11050355 56. Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022;23(8):1055-1065. doi:10.1016/S1470-2045(22)00335-7 57. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. doi:10.1016/S1470-2045(21)00591-X 58. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. doi:10.1186/s40425-018-0343-9 59. Grigor EJM, Fergusson D, Kekre N, et al. Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis. Transfus Med Rev. 2019;33(2):98-110. doi:10.1016/j.tmrv.2019.01.005 60. Nitschke L. The role of CD22 and other inhibitory co-receptors in B-cell activation. Curr Opin Immunol. 2005;17(3):290-297. doi:10.1016/j.coi.2005.03.005 61. Tang T, Cheng X, Truong B, Sun L, Yang X, Wang H. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther. 2021;219:107709. doi:10.1016/j.pharmthera.2020.107709 62. Dakappagari N, Ho SN, Gascoyne RD, Ranuio J, Weng AP, Tangri S. CD80 (B7.1) is expressed on both malignant B cells and nonmalignant stromal cells in non-Hodgkin lymphoma. Cytometry B Clin Cytom. 2012;82(2):112-119. doi:10.1002/cyto.b.20631 63. Deeks ED. Polatuzumab Vedotin: First Global Approval. Drugs. 2019;79(13):1467-1475. doi:10.1007/s40265-019-01175-0 64. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742. 65. Rosenbaum CA, Jung SH, Pitcher B, et al. Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance). Br J Haematol. 2019;185(1):53-64. doi:10.1111/bjh.15768 66. Hagenbeek A, Gadeberg O, Johnson P, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood. 2008;111(12):5486-5495. doi:10.1182/blood-2007-10-117671 67. Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119(16):3698-3704. doi:10.1182/blood-2011-09-378323 68. Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(20):3346-3353. doi:10.1200/JCO.2008.19.9117 69. Morschhauser F, Marlton P, Vitolo U, et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol Off J Eur Soc Med Oncol. 2010;21(9):1870-1876. doi:10.1093/annonc/mdq027 70. Tobinai K, Ogura M, Kobayashi Y, et al. Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma. Cancer Sci. 2011;102(2):432-438. doi:10.1111/j.1349-7006.2010.01809.x 71. Ganjoo KN, de Vos S, Pohlman BL, et al. Phase 1/2 study of ocaratuzumab, an Fc-engineered humanized anti-CD20 monoclonal antibody, in low-affinity FcγRIIIa patients with previously treated follicular lymphoma. Leuk Lymphoma. 2015;56(1):42-48. doi:10.3109/10428194.2014.911859 72. Leonard JP, Coleman M, Ketas JC, et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(16):3051-3059. doi:10.1200/JCO.2003.01.082 73. Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(12):2085-2093. doi:10.1200/JCO.2009.25.1900 74. Ogura M, Tobinai K, Hatake K, et al. Phase I study of inotuzumab ozogamicin (CMC-544) in Japanese patients with follicular lymphoma pretreated with rituximab-based therapy. Cancer Sci. 2010;101(8):1840-1845. doi:10.1111/j.1349-7006.2010.01601.x 75. Kebriaei P, Cutler C, de Lima M, et al. Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transplant. 2018;53(4):449-456. doi:10.1038/s41409-017-0019-y 76. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512 77. Salles G, Gopal AK, Minnema MC, et al. Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma. Clin Lymphoma Myeloma Leuk. 2019;19(5):275-284. doi:10.1016/j.clml.2018.12.013 78. Fanale M, Assouline S, Kuruvilla J, et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol. 2014;164(2):258-265. doi:10.1111/bjh.12630 79. Czuczman MS, Thall A, Witzig TE, et al. Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(19):4390-4398. doi:10.1200/JCO.2005.09.018 80. Armand P, Janssens A, Gritti G, et al. Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma. Blood. 2021;137(5):637-645. doi:10.1182/blood.2019004753 81. Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(25):4143-4149. doi:10.1200/JCO.2006.05.8198 82. Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(24):5696-5704. doi:10.1200/JCO.2005.14.803 83. Press OW, Unger JM, Rimsza LM, et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(3):314-320. doi:10.1200/JCO.2012.42.4101 84. Nastoupil LJ, Chin CK, Westin JR, et al. Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma. Blood Adv. 2022;6(4):1143-1151. doi:10.1182/bloodadvances.2021006240 85. Leonard JP, Schuster SJ, Emmanouilides C, et al. 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. Cancer. 2008;113(10):2714-2723. doi:10.1002/cncr.23890 86. Grant BW, Jung SH, Johnson JL, et al. A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Cancer. 2013;119(21):3797-3804. doi:10.1002/cncr.28299 87. Morschhauser F, Flinn IW, Advani R, et al. 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 Haematol. 2019;6(5):e254-e265. doi:10.1016/S2352-3026(19)30026-2 88. Diefenbach C, Kahl BS, McMillan A, et al. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. Lancet Haematol. 2021;8(12):e891-e901. doi:10.1016/S2352-3026(21)00311-2 89. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet Lond Engl. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8 90. Bannerji R, Arnason JE, Advani RH, et al. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Lancet Haematol. 2022;9(5):e327-e339. doi:10.1016/S2352-3026(22)00072-2 91. Hutchings M, Morschhauser F, Iacoboni G, et al. 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 Oncol Off J Am Soc Clin Oncol. 2021;39(18):1959-1970. doi:10.1200/JCO.20.03175 92. Subklewe M. BiTEs better than CAR T cells. Blood Adv. 2021;5(2):607-612. doi:10.1182/bloodadvances.2020001792 93. Tapia-Galisteo A, Compte M, Álvarez-Vallina L, Sanz L. When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy. Theranostics. 2023;13(3):1028-1041. doi:10.7150/thno.81494 94. Wu L, Seung E, Xu L, et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer. 2020;1(1):86-98. doi:10.1038/s43018-019-0004-z 95. Yao Y, Hu Y, Wang F. Trispecific antibodies for cancer immunotherapy. Immunology. 2023;169(4):389-399. doi:10.1111/imm.13636 96. Fayad L, Offner F, Smith MR, et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(5):573-583. doi:10.1200/JCO.2012.42.7211 97. Kolstad A, Illidge T, Bolstad N, et al. Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Adv. 2020;4(17):4091-4101. doi:10.1182/bloodadvances.2020002583 98. Palomba ML, Till BG, Park SI, et al. Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study. Clin Lymphoma Myeloma Leuk. 2022;22(7):e443-e451. doi:10.1016/j.clml.2021.12.010 99. Morschhauser F, Ghosh N, Lossos IS, et al. Obinutuzumab-atezolizumab-lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma: final analysis of a Phase Ib/II trial. Blood Cancer J. 2021;11(8):147. doi:10.1038/s41408-021-00539-8 100. Czuczman MS, Hess G, Gadeberg OV, et al. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157(4):438-445. doi:10.1111/j.1365-2141.2012.09086.x 101. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15(1):69-77. doi:10.1016/S1470-2045(13)70551-5 102. Czuczman MS, Leonard JP, Jung S, et al. 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 Oncol Off J Eur Soc Med Oncol. 2012;23(9):2356-2362. doi:10.1093/annonc/mdr620