Abstract
Follicular lymphoma (FL) is a disease often characterized by chronic and successive relapses after first-line chemoimmunotherapy. Although chemoimmunotherapy and combination therapy, such as lenalidomide with rituximab, are well established in the treatment sequence of FL, there is a need to streamline treatment options and determine placement of novel agents, such as chimeric antigen receptor T-cell therapy, an enhancer of zeste homolog 2 inhibitor, or a phosphoinositide 3 kinase inhibitor, into the treatment landscape. As such, the purpose of this review is to compare the safety profiles of approved agents in subsequent lines of therapy for relapsed or refractory FL and to assess how the management of adverse events may impact treatment choice.
References
Acrotech Biopharma. (2019). Zevalin (ibritumomab tiuxetan) package insert. https://zevalin.com/wp-content/uploads/2019/04/PI-ZEVALIN-092019.pdf
Baker, T., Nerle, S., Pritchard, J., Zhao, B., Rivera, V. M., Garner, A., & Gonzalvez, F. (2015). Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors. Oncotarget, 6(32), 32646–32655. https://doi.org/10.18632/oncotarget.5066
Bannerji, R., Arnason, J. E., Advani, R. H., Brown, J. R., Allan, J. N., Ansell, S. M.,...Topp, M. S. (2022). 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 Haematology, 9(5), e327–e339. https://doi.org/10.1016/s2352-3026(22)00072-2
Batlevi, C. L., Park, S. I., Phillips, T., Nastoupil, L., Amengual, J., Andorsky, D.,...Morschhauser, F. (2021). Interim analysis of the randomized phase 1b/3 study evaluating the safety and efficacy of tazemetostat plus lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma. Blood, 138(Supplement 1), 2207. https://doi.org/10.1182/blood-2021-148199
Batlevi, C. L., Sha, F., Alperovich, A., Ni, A., Smith, K., Ying, Z.,...Younes, A. (2020). Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer Journal, 10(7), 74. https://doi.org/10.1038/s41408-020-00340-z
Bayer. (2021). Aliqopa (copanlisib) package insert. http://labeling.bayerhealthcare.com/html/products/pi/Aliqopa_PI.pdf
Béguelin, W., Popovic, R., Teater, M., Jiang, Y., Bunting, K. L., Rosen, M.,...Melnick, A. M. (2013). EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell, 23(5), 677–692. https://doi.org/10.1016/j.ccr.2013.04.011
Bödör, C., Grossmann, V., Popov, N., Okosun, J., O’Riain, C., Tan, K.,...Fitzgibbon, J. (2013). EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood, 122(18), 3165–3168. https://doi.org/10.1182/blood-2013-04-496893
Budde, L. E., Sehn, L. H., Matasar, M., Schuster, S. J., Assouline, S., Giri, P.,...Bartlett, N. L. (2022). Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: A single-arm, multicentre, phase 2 study. Lancet Oncology, 23(8), 1055–1065. https://doi.org/10.1016/S1470-2045(22)00335-7
Budde, L. E., Sehn, L. H., Matasar, M. J., Schuster, S. J., Assouline, S., Giri, P.,...Bartlett, N. L. (2021). Mosunetuzumab monotherapy is an effective and well-tolerated treatment option for patients with relapsed/refractory (R/R) follicular lymphoma (FL) who have received ≥2 prior lines of therapy: Pivotal results from a phase I/II study. Blood, 138(Supplement 1), 127. https://doi.org/10.1182/blood-2021-145872
Casulo, C., Byrtek, M., Dawson, K. L., Zhou, X., Farber, C. M., Flowers, C. R.,...Friedberg, J. W. (2015). 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. Journal of Clinical Oncology, 33(23), 2516–2522. https://doi.org/10.1200/JCO.2014.59.7534
Celgene. (2021). Revlimid (lenalidomide) package insert. https://packageinserts.bms.com/pi/pi_revlimid.pdf
Chauhan, A. F., & Cheson, B. D. (2021). Copanlisib in the treatment of relapsed follicular lymphoma: Utility and experience from the clinic. Cancer Management Research, 13, 677–692. https://doi.org/10.2147/cmar.s201024
Cheson, B. D., O’Brien, S., Ewer, M. S., Goncalves, M. D., Farooki, A., Lenz, G.,...Dreyling, M. (2019). Optimal management of adverse events from copanlisib in the treatment of patients with non-Hodgkin lymphomas. Clinical, Lymphoma, Myeloma, and Leukemia, 19(3), 135–141. https://doi.org/10.1016/j.clml.2018.11.021
Dreyling, M., Ghielmini, M., Rule, S., Salles, G., Ladetto, M., Tonino, S. H.,…Jerkeman, M. (2021). Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 32(3), 298–308. https://doi.org/10.1016/j.annonc.2020.11.008
Dreyling, M., Santoro, A., Mollica, L., Leppä, S., Follows, G. A., Lenz, G.,...Zinzani, P. L. (2017). Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. Journal of Clinical Oncology, 35(35), 3898–3905. https://doi.org/10.1200/jco.2017.75.4648
Epizyme. (2020). Tazverik (tazemetostat) package insert. https://d2rkmuse97gwnh.cloudfront.net/a88aa6d6-3ca0-4362-a711-d53c45ae33ff/522a2033-f01b-422d-81b6-78692eb7a6da/522a2033-f01b-422d-81b6-78692eb7a6da_source__v.pdf
Fowler, N. H., Dickinson, M., Dreyling, M., Martinez-Lopez, J., Kolstad, A., Butler, J.,...Thieblemont, C. (2022). Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: The phase 2 ELARA trial. Nature Medicine, 28(2), 325–332. https://doi.org/10.1038/s41591-021-01622-0
Friedberg, J. W., Taylor, M. D., Cerhan, J. R., Flowers, C. R., Dillon, H., Farber, C. M.,...Link, B. K. (2009). Follicular lymphoma in the United States: First report of the national LymphoCare study. Journal of Clinical Oncology, 27(8), 1202–1208. https://doi.org/10.1200/jco.2008.18.1495
Gea-Banacloche, J. C. (2023). Infectious complications of chimeric antigen receptor (CAR) T-cell therapies. Seminars in Hematology, 60(1), 52–58. https://doi.org/10.1053/j.seminhematol.2023.02.003
Genentech. (2021). Rituxan (rituximab) package insert. https://www.gene.com/download/pdf/rituxan_prescribing.pdf
Genentech. (2022a). Gazyva (obinutuzumab) package insert. https://www.gene.com/download/pdf/gazyva_prescribing.pdf
Genentech. (2022b). Lunsumio (mosunetuzumab) package insert. https://www.gene.com/download/pdf/lunsumio_prescribing.pdf
Gilead. (2022). Gilead statement on Zydelig U.S. indication for follicular lymphoma and small lymphocytic leukemia. https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-zydelig-us-indication-for-follicular-lymphoma-and-small-lymphocytic-leukemia
Huntington, S. F., Appukkuttan, S., Wang, W., Du, Y., Hopson, S., & Babajanyan, S. (2022). Treatment patterns of follicular lymphoma in the United States: A claims analysis. Journal of Health Economics and Outcomes Research, 9(2), 115–122. https://doi.org/10.36469/001c.38070
Hutchings, M., Mous, R., Clausen, M. R., Johnson, P., Linton, K. M., Chamuleau, M. E. D.,...Lugtenburg, P. J. (2020). 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. Blood, 136(Supplement 1), 45–46. https://doi.org/10.1182/blood-2020-133820
Jacobson, C. A., Chavez, J. C., Sehgal, A. R., William, B. M., Munoz, J., Salles, G.,...Neelapu, S. S. (2022). Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): A single-arm, multicentre, phase 2 trial. Lancet Oncology, 23(1), 91–103. https://doi.org/10.1016/s1470-2045(21)00591-x
Javaruppa, K. K., Tsallos, D., & Heckman, C. A. (2018). A multiplexed screening assay to evaluate chemotherapy-induced myelosuppression using healthy peripheral blood and bone marrow. SLAS Discovery, 23(7), 687–696. https://doi.org/10.1177/2472555218777968
Jurczak, W., Zinzani, P. L., Cunningham, D., Yavrom, S., Huang, W., Gorbatchevsky, I., & Ribrag, V. (2021). Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL). Journal of Clinical Oncology, 39(15 suppl), TPS7573. https://doi.org/10.1200/JCO.2021.39.15_suppl.TPS7573
Kite Pharma. (2022). Yescarta (axicabtagene ciloleucel) package insert. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf
Leonard, J. P., Jung, S. H., Johnson, J., Pitcher, B. N., Bartlett, N. L., Blum, K. A.,...Cheson, B. D. (2015). Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). Journal of Clinical Oncology, 33(31), 3635–3640. https://doi.org/10.1200/jco.2014.59.9258
Leonard, J. P., Trneny, M., Izutsu, K., Fowler, N., Hong, X., Zhang, H.,...Gribben, J. (2019a). AUGMENT phase III study: Lenalidomide/rituximab (R2) improved efficacy over rituximab/placebo in relapsed/refractory follicular patients irrespective of POD24 status. Hematological Oncology, 37(S2), 114–115. https://doi.org/https://doi.org/10.1002/hon.75_2629
Leonard, J. P., Trneny, M., Izutsu, K., Fowler, N. H., Hong, X., Zhu, J.,...Gribben, J. G. (2019b). AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. Journal of Clinical Oncology, 37(14), 1188–1199. https://doi.org/10.1200/jco.19.00010
Link, B. K., Day, B. M., Zhou, X., Zelenetz, A. D., Dawson, K. L., Cerhan, J. R.,...Friedberg, J. W. (2019). Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: Data from the observational National LymphoCare Study. British Journal of Haematology, 184(4), 660–663. https://doi.org/10.1111/bjh.15149
Los-Arcos, I., Iacoboni, G., Aguilar-Guisado, M., Alsina-Manrique, L., Díaz de Heredia, C., Fortuny-Guasch, C.,...Ruiz-Camps, I. (2021). Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: A position paper. Infection, 49(2), 215–231. https://doi.org/10.1007/s15010-020-01521-5
Marcus, R., Davies, A., Ando, K., Klapper, W., Opat, S., Owen, C.,…Hiddemann, W. (2017). Obinutuzumab for the first-line treatment of follicular lymphoma. New England Journal of Medicine, 377(14), 1331–1344. https://doi.org/10.1056/NEJMoa1614598
Matasar, M. J., Capra, M., Özcan, M., Lv, F., Li, W., Yanez, E.,...Zinzani, P. L. (2021). Copanlisib + rituximab versus rituximab + placebo in patients with relapsed follicular (FL) or marginal zone lymphoma (MZL): Subset analysis from the phase III CHRONOS-3 trial. Journal of Clinical Oncology, 39(15_suppl), 7510. https://doi.org/10.1200/JCO.2021.39.15_suppl.7510
MEI Pharma, Inc. (2021). MEI Pharma and Kyowa Kirin announce data from the ongoing global phase 2 TIDAL study evaluating zandelisib as a single agent in patients with relapsed or refractory follicular lymphoma. https://www.kyowakirin.com/media_center/news_releases/2021/e20211130_01.html
Morschhauser, F., Tilly, H., Chaidos, A., McKay, P., Phillips, T., Assouline, S.,...Salles, G. (2020). Tazemetostat for patients with relapsed or refractory follicular lymphoma: An open-label, single-arm, multicentre, phase 2 trial. Lancet Oncology, 21(11), 1433–1442. https://doi.org/10.1016/S1470-2045(20)30441-1
National Cancer Institute. (2021). Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version. https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq
National Institutes of Health. (2021). SEER cancer stat facts: NHL — follicular lymphoma. https://seer.cancer.gov/statfacts/html/follicular.html
Ngu, H., Takiar, R., Phillips, T., Okosun, J., & Sehn, L. H. (2022). Revising the treatment pathways in lymphoma: New standards of care-How do we choose? American Society of Clinical Oncology Educational Book, 42, 1–14. https://doi.org/10.1200/EDBK_349307
Novartis Pharmaceuticals Corporation. (2022). Kymriah (tisagenlecleucel) package insert. https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf
Patel, K., Bailey, N., Miller, K., O’Connor, H., Yang, J., Lingaraj, T.,...Pagel, J. M. (2021). Trial in progress: SYMPHONY-2, a phase 2, single-arm, open-label, multicenter study of tazemetostat in combination with rituximab for the treatment of relapsed or refractory follicular lymphoma [poster 3541]. Annual Meeting and Exposition of the American Society of Hematology, Atlanta, GA.
Potnis, K. C., Di, M., Isufi, I., Gowda, L., Seropian, S. E., Foss, F. M.,…Huntington, S. F. (2023). Cost-effectiveness of chimeric antigen receptor T-cell therapy in adults with relapsed or refractory follicular lymphoma. Blood Advances, 7(5), 801–810. https://doi.org/10.1182/bloodadvances.2022008097
PR Newswire. (2021). Secura Bio announces Copiktra (duvelisib) strategic focus on T-cell lymphoma and voluntary U.S. withdrawal of the relapsed or refractory follicular lymphoma indication. https://www.prnewswire.com/news-releases/secura-bio-announces-copiktra-duvelisib-strategic-focus-on-t-cell-lymphoma-and-voluntary-us-withdrawal-of-the-relapsed-or-refractory-follicular-lymphoma-indication-301436834.html
Proudman, D., Nellesen, D., Gupta, D., Adib, D., Yang, J., & Mamlouk, K. (2021). A matching-adjusted indirect comparison of single-arm trials in patients with relapsed/refractory follicular lymphoma who received at least 2 prior systemic treatments: Tazemetostat was associated with a lower risk for safety outcomes versus the PI3-kinase inhibitors idelalisib, duvelisib, copanlisib, and umbralisib [poster]. Advances in Therapy, 39, 1678–1696. https://link.springer.com/article/10.1007/s12325-022-02054-z
Qualls, D., & Salles, G. (2022). Prospects in the management of patients with follicular lymphoma beyond first-line therapy. Haematologica, 107(1), 19–34. https://doi.org/10.3324/haematol.2021.278717
Rodgers, T. D., Casulo, C., Boissard, F., Launonen, A., Parreira, J., & Cartron, G. (2021). Early relapse in first-line follicular lymphoma: A review of the clinical implications and available mitigation and management strategies. Oncology and Therapy, 9(2), 329–346. https://doi.org/10.1007/s40487-021-00161-5
Salles, G. (2020). How do I sequence therapy for follicular lymphoma? Hematology, 2020(1), 287–294. https://doi.org/10.1182/hematology.2020000156
Salles, G., Tilly, H., Chaidos, A., McKay, P., Phillips, T. J., Assouline, S. E.,...Morschhauser, F. (2020). Analyzing efficacy outcomes from the phase 2 study of single-agent tazemetostat as third-line therapy in patients with relapsed or refractory follicular lymphoma to identify predictors of response. Blood, 136(suppl 1), 47–49. https://ashpublications.org/blood/article/136/Supplement%201/47/471807/Analyzing-Efficacy-Outcomes-from-the-Phase-2-Study
Sehn, L. H., Trněný, M., Bouabdallah, K., Dueck, G., Gribben, J. G., Lugtenburg, P. J.,...Cheson, B. D. (2019). Sustained overall survival benefit of obinutuzumab plus bendamustine followed by obinutuzumab maintenance compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: Final results of the gadolin study. Blood, 134(Supplement_1), 2822. https://doi.org/10.1182/blood-2019-123422
Skarbnik, A. Z., & Patel, K. (2023). Treatment selection for patients with relapsed or refractory follicular lymphoma. Frontiers in Oncology, 13, 1120358. https://doi.org/10.3389/fonc.2023.1120358
Sun, L. L., Ellerman, D., Mathieu, M., Hristopoulos, M., Chen, X., Li, Y.,...Ebens, A. J. (2015). Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Science Translational Medicine, 7(287), 287ra270. https://doi.org/10.1126/scitranslmed.aaa4802
Tan, D., Horning, S. J., Hoppe, R. T., Levy, R., Rosenberg, S. A., Sigal, B. M.,...Advani, R. H. (2013). Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: The Stanford University experience. Blood, 122(6), 981–987. https://doi.org/10.1182/blood-2013-03-491514
TG Therapeutics. (2022). TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL [press release]. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-voluntary-withdrawal-blasnda-u2-treat#:~:text=%C2%AB%20Back-,TG%20Therapeutics%20Announces%20Voluntary%20Withdrawal%20of%20the%20BLA%2FsNDA%20for,Patients%20with%20CLL%20and%20SLL&text=NEW%20YORK%2C%20April%2015%2C%202022,)%20%2D%2D%20TG%20Therapeutics%2C%20Inc
Thieblemont, C., Phillips, T., Ghesquieres, H., Cheah, C. Y., Clausen, M. R., Cunningham, D.,...Lugtenburg, P. J. (2022). Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II trial. Journal of Clinical Oncology, 41(12), 2238–2247. https://doi.org/10.1200/jco.22.01725
US Food and Drug Administration. (2024a). FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-relapsed-or-refractory-follicular-lymphoma
US Food and Drug Administration. (2024b). FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma
US Food and Drug Administration. (2022). Phosphatidylinositol 3-kinase (PI3K) inhibitors in hematologic malignancies. FDA Oncologic Drugs Advisory Committee briefing document. https://www.fda.gov/media/157762/download
Witzig, T. E., Nowakowski, G. S., Habermann, T. M., Goy, A., Hernandez-Ilizaliturri, F. J., Chiappella, A.,…Czuczman, M. S. (2015). A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma. Annals of Oncology, 26(8), 1667–1677. https://doi.org/10.1093/annonc/mdv102
Wudhikarn, K., & Perales, M. A. (2022). Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transplant, 57(10), 1477–1488. https://doi.org/10.1038/s41409-022-01756-w
Yáñez, L., Sánchez-Escamilla, M., & Perales, M. A. (2019). CAR T cell toxicity: Current management and future directions. Hemasphere, 3(2), e186. https://doi.org/10.1097/hs9.0000000000000186
Zhou, S., Liu, M., Ren, F., Meng, X., & Yu, J. (2021). The landscape of bispecific T cell engager in cancer treatment. Biomarker Research, 9(1), 38. https://doi.org/10.1186/s40364-021-00294-9
