Current treatment options for relapsed and refractory diffuse large B-cell lymphoma: literature review and clinical case

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive non-Hodgkin’s lymphoma. Despite advances in therapy, including targeted therapy, 30–40 % of patients experience a primary refractory or relapsed disease with a poor prognosis.

This publication presents a literature review of current approaches to treating patients with refractory and relapsed (r / r) DLBCL and a clinical case of a patient with r / r DLBCL using multiple lines of therapy, including CAR-T cell therapy (4SCAR70, anti-CD70) and bispecific antibodies (glofitamab). During glofitamab therapy, the patient developed loss of CD20 expression, which is one of the mechanisms of resistance to anti-CD20 targeted therapy and occurs in 34 % of patients with progression against bispecific antibodies. Loss of CD20 expression limits further use of anti-CD20 targeted therapy, including re-use of glofitamab and other CD20 / CD3 bispecific antibodies. Five courses of VIPOR followed by allogeneic hematopoietic stem cell transplantation were administered as salvage therapy. At the time of the most recent assessment, the achieved complete response with complete donor chimerism is maintained, and the patient is under dynamic observation for three years.

There is currently no standard treatment strategy for patients with loss of CD20 expression after therapy with bispecific antibodies. Allogeneic hematopoietic stem cell transplantation is a potential therapeutic option for this category of patients. Alternative treatment strategies include the use of antibody conjugates directed at CD79b (polatuzumab vedotin) or CD19 (loncastuximab tesirin), a combination of lenalidomide and tafasitamab, as well as targeted agents depending on the lymphoma molecular subtype.

This clinical case demonstrates the possibility of achieving a complete response in a patient with refractory and relapsed DLBCL following loss of CD20 expression during glofitamab therapy. Treatment of these patients requires a personalized approach based on prior therapies, disease status, expression of target antigens, and the availability of therapeutic options. Further research is needed to determine the optimal treatment sequence, develop strategies to overcome resistance, and identify alternative therapeutic targets.

About the authors

Elizaveta N. Kodrul

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Author for correspondence.
Email: kodrul.liza@mail.ru
ORCID iD: 0009-0009-7940-1555
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

S. A. Volchenkov

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0002-2463-2024
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

L. V. Filatova

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia; North-Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0002-0728-4582
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758; 41 Kirochnaya St., Saint Petersburg 191015

A. A. Lomazov

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia; Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0009-0007-3826-8386
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758; 2 Litovskaya St., Saint Petersburg 194100

A. L. Muravtseva

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0002-4221-4248
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

I. V. Ishmatova

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0009-0004-2898-9823
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

A. A. Zverkova

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0009-0008-8457-0487
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

N. S. Kolupaev

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0002-0291-4928
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

A. O. Eliseeva

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0009-0009-4176-6444
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

S. S. Elkhova

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0002-1691-0549
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

L. A. Kramynin

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0003-4542-8353
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

A. G. Kolgotina

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0009-0001-2174-9083
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

T. Yu. Semiglazova

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0002-4305-6691
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

I. S. Zyuzgin

National Medical Research Center of Oncology named after N. N. Petrov, Ministry of Health of Russia

Email: kodrul.liza@mail.ru
ORCID iD: 0000-0001-9597-4593
Russian Federation, 68 Leningradskaya St., Pesochny, Saint Petersburg 197758

References

  1. Levashov A.S., Valiev T.T., Kovrigina A.M. et al. Diagnosis and treatment of diffuse large B cell lymphoma in children and adults (review of literature). Sovremennaya onkologiya = Journal of Modern Oncology 2015;17(3):30–41. (In Russ.).
  2. Valiev T.T., Popa A.V., Levashov A.S. et al. Non-Hodgkin’s lymphomas in children: 25-year clinical experience. Klinicheskaya onkogematologiya. Fundamentalnye issledovaniya i klinicheskaya praktika = Clinical Oncohematology. Basic Research and Clinical Practice 2016;9(4):420–37. (In Russ.). doi: 10.21320/2500-2139-2016-9-4-420-437
  3. Kesireddy M., Lunning M. Relapsed or refractory diffuse large B-cell lymphoma: “dazed and confused”. Oncology (Williston Park) 2022;36(6):366–75. doi: 10.46883/2022.25920963
  4. Fabbri N., Mussetti A., Sureda A. Second-line treatment of diffuse large B-cell lymphoma: evolution of options. Semin Hematol 2023;60(5):305–12. doi: 10.1053/j.seminhematol.2023.12.001
  5. Sehn L.H., Salles G. Diffuse large B-cell lymphoma. N Engl J Med 2021;384(9):842–58. doi: 10.1056/NEJMra2027612
  6. Valiev T.T. Clinical characteristics and treatment results of pediatric relapsed/refractory non-Hodgkin’s lymphomas. Onkogematologiya = Oncohematology 2018;13(2):21–31. (In Russ.). doi: 10.17650/1818-8346-2018-13-2-21-31
  7. Salles G., Duell J., González Barca E. et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol 2020;21(7):978–88. doi: 10.1016/S1470-2045(20)30225-4
  8. Brooks T.R., Zabor E.C., Bedelu Y.B. et al. Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab. Blood 2025;146(18):2177–88. doi: 10.1182/blood.2025029117
  9. Caimi P.F., Ai W., Alderuccio J.P. et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2021;22(6):790–800. doi: 10.1016/S1470-2045(21)00139-X
  10. Gupta S., Bachanova V. CD19-directed chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma: lessons learned from clinical trials and real world evidence. Leuk Lymphoma 2025;66(14):2588–600. doi: 10.1080/10428194.2025.2560082
  11. Chow V.A., Shadman M., Gopal A.K. Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood 2018;132(8):777–81. doi: 10.1182/blood-2018-04-839217
  12. Bock A.M., Epperla N. Therapeutic landscape of primary refractory and relapsed diffuse large B-cell lymphoma: recent advances and emerging therapies. J Hematol Oncol 2025;18(1):68. doi: 10.1186/s13045-025-01702-5
  13. Deschênes-Simard X., Bromberg M., Devlin S.M. et al. Comparative real-world outcomes of CD19-directed CAR T-cell therapies in large B-cell lymphoma. Blood Adv 2025;9(21):5571–84. doi: 10.1182/bloodadvances.2025016778
  14. Westin J.R., Oluwole O.O., Kersten M.J. et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med 2023;389(2):148–57. doi: 10.1056/NEJMoa2301665
  15. Oluwole O.O., Neelapu S.S., Ray M.D. et al. Network meta-analysis of CAR T-cell therapy for the treatment of 3L+ R/R LBCL after using published comparative studies. Expert Rev Anticancer Ther 2024;24(6):457–65. doi: 10.1080/14737140.2024.2343801
  16. Schuster S.J., Tam C.S., Borchmann P. et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2021;22(10):1403–15. doi: 10.1016/S1470-2045(21)00375-2
  17. Kamdar M., Solomon S.R., Arnason J. et al. Lisocabtagene maraleucel versus standard of care for second-line relapsed/refractory large B-cell lymphoma: 3-year follow-up from the randomized, phase III TRANSFORM study. J Clin Oncol 2025;43(24):2671–78. doi: 10.1200/JCO-25-00399
  18. Abramson J.S., Palomba M.L., Gordon L.I. et al. Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood 2024;143(5):404–16. doi: 10.1182/blood.2023020854
  19. Konoplya N.E., Kalenik V.A., Dziameshka P.D. et al. CAR-T cell therapy in real-world clinical practice: an experience of the N.N. Alexandrov National Cancer Centre of Belarus. Klinicheskaya onkogematologiya. Fundamentalnye issledovaniya i klinicheskaya praktika = Clinical Oncohematology. Basic Research and Clinical Practice 2025;18(4):305–14. doi: 10.21320/2500-2139-2025-18-4-305-314
  20. Zhao D., Ruan J., Wei C. et al. Clinical outcome and immunophenotype of axicabtagene ciloleucel (axi-cel) and relmacabtagene autoleucel (relma-cel) in relapsed/refractory large B-cell lymphoma on Chinese population: a single-center experience. Ann Hematol 2025;104(10):5151–62. doi: 10.1007/s00277-025-06541-5
  21. Tang L., Cai D., Yan X., Mo W. Second-line chimeric antigen receptor T-cell therapy versus standard of care in relapsed or refractory large B-cell lymphoma: a systematic review and meta-analysis. Cancer 2026;132(4):e70317. doi: 10.1002/cncr.70317
  22. Staiger A.M., Ziepert M., Horn H. 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. J Clin Oncol 2017;35(22):2515–26. doi: 10.1200/JCO.2016.70.3660
  23. Davies A.J., Barrans S., Stanton L. et al. Differential efficacy from the addition of bortezomib to R-CHOP in diffuse large B-cell lymphoma according to the molecular subgroup in the REMoDL-B study with a 5-year follow-up. J Clin Oncol 2023;41(15):2718–23. doi: 10.1200/JCO.23.00033
  24. Nowakowski G.S., Chiappella A., Gascoyne RD. et al. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol 2021;39(12):1317–28. doi: 10.1200/JCO.20.01366
  25. Dickinson M.J., Carlo-Stella C., Morschhauser F. et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2022;387(24):2220–31. doi: 10.1056/NEJMoa2206913
  26. Rushton C.K., Arthur S.E., Alcaide M. et al. Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma. Blood Adv 2020;4(13):2886–98. doi: 10.1182/bloodadvances.2020001696
  27. Gao T., Suolitiken D., Yang C. et al. Assessing the effectiveness of etoposide treatment in adult haemophagocytic lymphohistiocytosis: a systematic review and meta-analysis. Clin Exp Med 2025;25(1):58. doi: 10.1007/s10238-025-01570-w
  28. Zhou D., Huang X., Zhu L. et al. Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China. Blood 2025;146(3):318–27. doi: 10.1182/blood.2024026139
  29. Valiev T.T., Kovrigina A.M., Kluchagina Yu.I., Senderovich A.I. Cytogenetic research experience in pediatric non-Hodgkin’s lymphomas. Onkopediatriya = Oncopediatrics 2016;3(2):125–32. (In Russ.). doi: 10.15690/onco.v3i2.1547
  30. Brudno J.N., Maus M.V., Hinrichs C.S. CAR T cells and T-cell therapies for cancer: a translational science review. JAMA 2024;332(22):1924–35. doi: 10.1001/jama.2024.19462
  31. Lin Y., Luo S., Wei J. et al. Limitations of CAR-T-cell therapy in hematologic malignancies: focusing on antigen escape and T-cell dysfunction. Int J Mol Sci 2025;26(19):9669. doi: 10.3390/ijms26199669
  32. Shah N.N., Fry T.J. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol 2019;16(6):372–85. doi: 10.1038/s41571-019-0184-6
  33. Beider K., Itzhaki O., Schachter J. et al. Molecular and functional signatures associated with CAR T cell exhaustion and impaired clinical response in patients with B cell malignancies. Cells 2022;11(7):1140. doi: 10.3390/cells11071140
  34. Casey M., Lee C., Kwok W.Y. et al. Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy. Haematologica 2024;109(3):787–98. doi: 10.3324/haematol.2023.283758
  35. Li J.P., Wang P., Liu F.F. et. al. Assessment of the efficacy and prognostic value of 18F-FDG PET-CT using Deauville 5-point scale and ΔSUVmax methods in diffuse large B-cell lymphoma patients. Medicine (Baltimore) 2025;104(36):e44067. doi: 10.1097/MD.0000000000044067
  36. Tilly H., Morschhauser F., Sehn L.H. et. al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 2022;386(4):351–63. doi: 10.1056/NEJMoa2115304
  37. Kim T.M., Taszner M., Novelli S. et al. ELM-2 Investigators. Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma [published correction appears in Ann Oncol 2025;36(3):352]. Ann Oncol 2024;35(11):1039–47. doi: 10.1016/j.annonc.2024.08.2239
  38. Carlo-Stella C. Relapse after glofitamab, a novel unmet medical need with high rates of CD20 loss. Br J Haematol 2024;205(1): 17–9. doi: 10.1111/bjh.19503
  39. Ladbury C., Thiruvengadam S.K., Othman T. et al. Role of salvage radiation treatment of relapses in relapsed/refractory diffuse large B cell lymphoma post-autologous stem cell transplant. Int J Radiat Oncol Biol Phys 2022;113(3):594–601. doi: 10.1016/j.ijrobp.2022.02.015
  40. Tarella C., Sammassimo S., Frassoni S. et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation in relapsed/refractory B-cell non-Hodgkin lymphoma: an Italian multicenter collaborative study. Transplant Cell Ther 2025;31(10):806.e1–19. doi: 10.1016/j.jtct.2025.06.004
  41. Zurko J., Ramdial J., Shadman M. et al. Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma. Haematologica 2023;108(1):98–109. doi: 10.3324/haematol.2022.281242
  42. Barone A., De Philippis C., Stella F. et al. Allogeneic transplantation after failure of chimeric antigen receptor-T cells and exposure to bispecific antibodies: feasibility, safety and survival outcomes. Br J Haematol 2025;207(3):956–64. doi: 10.1111/bjh.70010
  43. Min G.J., Jeon Y.W., Kim T.Y. et al. The salvage role of allogeneic hematopoietic stem-cell transplantation in relapsed/refractory diffuse large B cell lymphoma. Sci Rep 2023;13(1):17496. doi: 10.1038/s41598-023-44241-0
  44. Di Blasi R., Le Gouill S., Bachy E. et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood 2022;140(24):2584–93. doi: 10.1182/blood.2022016945
  45. Sorin M., Okde R., Goulet M. et al. Chimeric antigen receptor T-cell therapy and bispecific antibody sequence for large B-cell lymphoma: a systematic review and meta-analysis. Lancet Haematol 2026;13(2):e86–97. doi: 10.1016/S2352-3026(25)00318-7
  46. Sayyed A., Chen C., Gerbitz A. et al. Pretransplant blinatumomab improves outcomes in B cell acute lymphoblastic leukemia patients who undergo allogeneic hematopoietic cell transplantation. Transplant Cell Ther 2024;30(5):520.e1–12. doi: 10.1016/j.jtct.2024.03.004

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