王思淇,邢宏运

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）是成人最常见的侵袭性非霍奇金淋巴瘤。R-CHOP（利妥昔单抗联合环磷酰胺、多柔比星、长春新碱及泼尼松）作为一线标准治疗的广泛应用显著提升了DLBCL患者的整体疗效，初治患者完全缓解率（complete remission rate，CRR）可达70%～80%，5年总生存率（overall survival，OS）为60%～70%[1]。然而，仍有约30%～40%的患者对一线治疗表现为原发耐药或最终出现疾病复发，进展为复发/难治性（relapsed/refractory，R/R）DLBCL。此类患者整体预后极差，2年总生存率仅为20%～40%[2,3]，疾病复发与难治仍是当前临床亟待解决的重要挑战。

弥漫性大B细胞淋巴瘤；复发/难治性；CAR-T疗法；双特异性抗体；抗体药物偶联物；靶向治疗；免疫治疗；预后因素

[1] Bock M A,Epperla N.Therapeutic landscape of primary refractory and relapsed diffuse large B-cell lymphoma:Recent advances and emerging therapies[J].J Hematol Oncol,2025,18(1):68. [2] Yang L,Klaus S B.Diffuse large B-cell lymphoma:2019 update on diagnosis,risk stratification,and treatment[J].Am J Hematol,2019,94(5):604-616. [3] Jing Z,Yan G,Baoan C,et al.Drug-Resistance Mechanism and New Targeted Drugs and Treatments of Relapse and Refractory DLBCL[J].Cancer Manag Res,2023,15:245-255. [4] 中华医学会血液学分会淋巴细胞疾病学组,中国临床肿瘤学会(CSCO)淋巴瘤专家委员会.老年弥漫大B细胞淋巴瘤诊断与治疗中国专家共识(2024年版)[J].中华血液学杂志,2024,45(4):322-329. [5] Tresckow V B,Abrisqueta P,Zamanillo I,et al.Prognostic Factors and Effect Modifiers in Patients With Relapse or Refractory Diffuse Large B-Cell Lymphoma After Two Lines of Therapy:A Systematic Literature and Expert Clinical Review[J].Eur J Haematol,2025, 115(2):104-116. [6] 赵洁,姜言,郝思国.弥漫大B细胞淋巴瘤患者临床特征及预后分析[J].上海交通大学学报(医学版),2023,43(10):1282-1288. [7] Guo Y,Lian J,Chen Y,et al.Factors affecting refractoriness or recurrence in diffuse large B-cell lymphoma:development and validation of a novel predictive nomogram[J].Hematology,2025,30(1):2445395. [8] A N J,W G S,J K S,et al.Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone[J].J Clin Oncol,2012,30(28):3452-3459. [9] F A H,Matthew M,Lawrence L,et al.Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression- Free Survival After Autologous Stem-Cell Transplantation[J].J Clin Oncol,2017,35(1):24-31. [10] Jia W,Min X,Zekai M,et al.Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT[J].Signal Transduct Target Ther,2022,7(1):101. [11] Roland S,W G W,Wei D H,et al.Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma[J].N Engl J Med,2018,378(15):1396-1407. [12] 陈馨蕊.复发/难治弥漫大B细胞淋巴瘤免疫治疗的作用及机制研究[D].北京:北京协和医学院,2025. [13] Walker J S,Wenzl K,Novak J P,et al.Integrated genomics with refined cell-of-origin subtyping distinguishes subtype-specific mechanisms of treatment resistance and relapse in diffuse large B-cell lymphoma[J].Blood Cancer J,2025,15(1):120. [14] Wang L,Li L R.R-CHOP resistance in diffuse large B-cell lymphoma:biological and molecular mechanisms[J].Chin Med J, 2020,134(3):253-260. [15] Coughlin A C,Chahar D,Lekakis M,et al.Bruton's tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax[J].Blood Cancer J,2025,15(1):9. [16] Han X,Sui J,Nie K,et al.Tumor evolution analysis uncovered immune-escape related mutations in relapse of diffuse large B-cell lymphoma[J].Leukemia,2024,38(10):2276-2280. [17] Christian G,Eric N D V.How I manage patients with relapsed/refractory diffuse large B cell lymphoma[J].Br J Haematol,2018, 182(5):633-643. [18] Christian G,Bertram G,Nicolas M,et al.Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era[J].J Clin Oncol,2010,28(27):4184-4190. [19] Manali K,R S S,Jon A,et al.Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma(TRANSFORM):results from an interim analysis of an open-label,randomised,phase 3 trial[J].Lancet,2022,399(10343):2294-2308. [20] 郑锐年,林顺欢,林钦雄,等.R-GEMOX方案二线治疗弥漫大B细胞淋巴瘤的临床疗效观察[J].中国医学工程,2016,24(3):9-11. [21] 武莉丽,史俐,李炜静,等.西达本胺联合DICE方案治疗复发/难治弥漫大B细胞淋巴瘤的疗效和生存分析[J].中国实验血液学杂志,2025,33(2):373-378. [22] Sarkozy C,Sehn H L.Management of relapsed/refractory DLBCL[J].Best Pract Res Clin Haematol,2018,31(3):209-216. [23] E N D V,N S,N M,et al.Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study[J].Bone Marrow Transplant,2016,51(1):51-57. [24] Philip T,Guglielmi C,Hagenbeek A,et al.Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma[J].N Engl J Med,1995,333(23):1540-1545. [25] Epperla N,Kumar A,Abutalib S A,et al.ASTCT Clinical Practice Recommendations for Transplantation and Cellular Therapies in Diffuse Large B Cell Lymphoma[J].Transplant Cell Ther,2023,29(9):548-555. [26] W J R K V,Carmen C,C H S,et al.Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation:an analysis of the European Group for Blood and Marrow Transplantation Registry[J].J Clin Oncol,2011,29(10):1342-1348. [27] H W W,M R Y,Roland S,et al.Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma[J].Nat Med,2015, 21(8):922-926. [28] Andre G,Radhakrishnan R,Nilanjan G,et al.Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL[J].Blood,2019,134(13):1024-1036. [29] Xianggui Y,Xian L,Yurong H,et al.Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma[J]. Front Immunol,2022,13:1015081. [30] S M D,W A R,F J S,et al.Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma[J].J Clin Oncol,2017,35(8):826-833. [31] Kalakonda N,Maerevoet M,Cavallo F,et al.Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma(SADAL):a single-arm,multinational,multicentre,open-label,phase 2 trial[J].Lancet Haematol,2020,7(7):e511-e522. [32] Xu-Wen G,Hua-Qing W,Wei-Wei B,et al.Novel HDAC inhibitor Chidamide synergizes with Rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20[J].Cell Death Dis,2020,11(1):20. [33] Morschhauser F,Salles G,McKay P,et al.Interim report from a phase 2 multicenter study of tazemetostat,an EZH2 inhibitor,in patients with relapsed or refractory B-cell non-Hodgkin lymphomas[J].Hematol Oncol,2017,35(S2):24-25. [34] H L S,F A H,R C F,et al.Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma[J].J Clin Oncol,2020, 38(2):155-165. [35] Wang Y W,Tsai X C,Hou H A,et al.Polatuzumab vedotin-based salvage immunochemotherapy as third-line or beyond treatment for patients with diffuse large B-cell lymphoma:a real-world experience[J].Ann Hematol,2022,101(2):349-358. [36] Wilson K,Chiodi F,Paine A,et al.Loncastuximab Tesirine Versus Polatuzumab Vedotin Plus Bendamustine and Rituximab in Relapsed/Refractory DLBCL After≥2 Lines of Therapy:Matching-Adjusted Indirect Comparison[J].Adv Ther,2025,42(5):2673-2692. [37] Zelikson V,Gurumurthi A,Sawalha Y,et al.Loncastuximab in high-risk and heavily pretreated relapsed/refractory diffuse large B-cell lymphoma:a realworld analysis from 21 US centers. Haematologica.2025;110(3):706-714. [38] Zhao W,et al.First data from phase 1b/2 EPCORE NHL-4:Epcoritamab(Epcor)in Chinese patients(Pts)with relapsed or refractory diffuse large B-cell lymphoma(R/R DLBCL)[J].J Clin Oncol,2025,43(16_suppl):e19001. [39] Dickinson M J,Carlo-Stella C,Morschhauser F,et al.Fixed-Duration Glofitamab Monotherapy Continues to Demonstrate Durable Responses in Patients with Relapsed or Refractory Large B-Cell Lymphoma:3-Year Follow-up from a Pivotal Phase II Study[J].Blood, 2024,144(S1):865. [40] Gurion R,Guz D,Kedmi M,et al.Efficacy and safety of Glofitamab in patients with R/R DLBCL in real life setting-a retrospective study[J].Ann Hematol,2025,104(7):2513-2519. [41] Brooks T R,Zabor C E,Bedelu Y,et al.Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab[J].Blood,2025,146(18):2177-2188. [42] Yan Q,Xiaohui H,Xinrui C,et al.Efficacy and safety of PD-1 monoclonal antibody plus rituximab in relapsed/refractory diffuse large B cell lymphoma patients[J].Eur J Haematol,2023,111(3):356-364. [43] Chen X,Qin Y,Xue X,et al.Multi-omics analysis and response prediction of PD-1 monoclonal antibody containing regimens in patients with relapsed/refractory diffuse large B-cell lymphoma[J].Cancer Immunol Immunother,2024,73(12):250. [44] JM A,Kaljit B,Roger H,et al.Expression of PD-1(CD279)and FoxP3 in diffuse large B-cell lymphoma[J].Virchows Arch,2014, 465(3):351-358. [45] Neelapu S S,Jacobson C A,Ghobadi A,et al.Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma[J].Blood,2023,141(19):2307-2315. [46] JS S,R M B,S C T,et al.Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma[J].N Engl J Med,2019, 380(1):45-56. [47] Abramson J S,Palomba M L,Gordon L I,et al.Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas(TRANSCEND NHL 001):a multicentre seamless design study[J].Lancet,2020,396(10254):839-852. [48] L F L,B D M,A C J,et al.Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma[J].N Engl J Med,2021, 386(7):640-654. [49] R J W,O O O,JoséM K,et al.Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma[J].N Engl J Med,2023,389(2):148-157. [50] Lee D W,Santomasso B D,Locke F L,et al.ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells[J].Biol Blood Marrow Transplant,2019,25(4):625-638. [51] N N S,J T F.Mechanisms of resistance to CAR T cell therapy[J].Nat Rev Clin Oncol,2019,16(6):372-385. [52] Norasetthada L,Diaz J,Lv F,et al.Updated Results from the Phase 2 Waveline-004 Study of Zilovertamab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma[J].Blood,2024,144(S1):1738. [53] Gaballa S,Hou J Z,Devata S,et al.Evaluation of AZD0486,a Novel CD19xCD3 T-Cell Engager,in Relapsed/Refractory Diffuse Large B-Cell Lymphoma in an Ongoing First-in-Human Phase 1 Study:High Complete Responses Seen in CAR-T-Naive and CAR-T-Exposed Patients[J].Blood,2024,144(S1):868. [54] Michot J M,Morschhauser F,Ferrari S,et al.Longer Follow-up of Golcadomide(GOLCA),a Cereblon E3 Ligase Modulator (CELMoD™)Agent±Rituximab(RTX),in Patients with Relapsed/Refractory(R/R)Diffuse Large B-Cell Lymphoma(DLBCL)[J]. Blood, 2024,144(S1):869. [55] Catherine T,Javier M,Alessandra T,et al.Iberdomide(CC-220)Monotherapy or in Combination with an Anti-CD20 Monoclonal Antibody As Effective Therapy in Patients with Relapsed/Refractory Lymphoma:Early Results from a Phase 1/2 Study[J].Blood,2022, 140(S1):569-572.

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