Efficacy and safety of salvage therapeutic regimens for the relapsed/refractory diffuse large B cell lymphoma: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

GAN Zhichao , GAO Jiajia , ZHU Jianhua ,  XIONG Yongfen

Department of Clinical Laboratory, Wuhan No.1 Hospital, Wuhan 430022, P. R. China;

Corresponding author：

XIONG Yongfen, Email: xiongyf0829@163.com

Keywords：

Relapsed/refractory diffuse large B cell lymphoma (r/rDLBCL); Salvage therapeutic regimens; Network meta-analysis; Immunochemotherapy; Autologous stem cell transplantation (ASCT)

DOI：

10.7507/1672-2531.202305062

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To analyze the efficacy and safety of various treatment strategies for patients with refractory/recurrent diffuse large B-cell lymphoma (r/r-DLBCL) by network meta-analysis. Methods The PubMed, EMbase and Cochrane Library databases were searched to collect randomized controlled trials (RCTs) and clinical controlled trials related to the objectives of the study from inception to November 16^th, 2022. After two investigators independently screened the literature, extracted data and evaluated the risk of bias of the included studies, a network meta-analysis was performed using R 4.2.2 software. Results A total of 8 RCTs and 11 non-randomized controlled trials were included, involving 2 559 cases. The treatment regimen included chemotherapy, immunochemotherapy, chemotherapy combined with ADC, immunochemotherapy combined with ADC, ASCT based regimen, CAR-T based regimen, ASCT combined with CAR-T, immunomodulators, small molecule inhibitors, and rituximab combined with small molecule inhibitors. The ranking probability results showed that the top three complete remission (CR) rates among all schemes were ASCT combined with CAR-T, chemotherapy combined with ADC, and immune modulators; The top three overall response rates (ORR) were chemotherapy combined with ADC, ASCT combined with CAR-T, and ASCT. The CAR-T regimen had a higher rate of severe neutropenia; The severe thrombocytopenia rate of ASCT regimen was relatively high; There was no significant difference in the incidence of SAEs among the other options. Conclusion ASCT combined with CAR-T and chemotherapy combined with ADC have the best therapeutic effects on r/r-DLBCL. However, the specific protocol to be adopted requires clinical doctors to combine actual conditions, comprehensively consider the efficacy and side effects, and develop personalized treatment strategies for r/r-DLBCL patients.

Citation： GAN Zhichao, GAO Jiajia, ZHU Jianhua, XIONG Yongfen. Efficacy and safety of salvage therapeutic regimens for the relapsed/refractory diffuse large B cell lymphoma: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2023, 23(9): 1011-1016. doi: 10.7507/1672-2531.202305062 Copy

1.	Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev, 2019, 10(10): ED000142.
2.	王浩, 唐晓宇, 王和平, 等. ROBINS-I: 评估非随机干预性研究偏倚风险的新工具. 中国循证心血管医学杂志, 2018, 10(7): 789-793.
3.	Mey UJ, Olivieri A, Orlopp KS, et al. DHAP in combination with rituximab vs. DHAP alone as salvage treatment for patients with relapsed or refractory diffuse large B-cell lymphoma: a matched-pair analysis. Leuk Lymphoma, 2006, 47(12): 2558-2566.
4.	Avilés A, Neri N, Huerta-Guzmán J, et al. ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk, 2010, 10(2): 125-128.
5.	Assouline SE, Nielsen TH, Yu S, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood, 2016, 128(2): 185-194.
6.	Vellenga E, van Putten WL, van 't Veer MB, et al. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood, 2008, 111(2): 537-543.
7.	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. N Engl J Med, 1995, 333(23): 1540-1545.
8.	Morschhauser F, Illidge T, Huglo D, et al. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood, 2007, 110(1): 54-58.
9.	Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood, 2004, 103(10): 3684-3688.
10.	Sieniawski M, Staak O, Glossmann JP, et al. Rituximab added to an intensified salvage chemotherapy program followed by autologous stem cell transplantation improved the outcome in relapsed and refractory aggressive non-Hodgkin lymphoma. Ann Hematol, 2007, 86(2): 107-115.
11.	张慕晨, 钱樱, 郝杰, 等. 二线方案治疗98例复发难治弥漫大B细胞淋巴瘤的疗效及预后分析. 中华血液学杂志, 2017, 38(6): 511-516.
12.	Czuczman MS, Trněný M, Davies A, et al. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res, 2017, 23(15): 4127-4137.
13.	Hamadani M, Gopal AK, Pasquini M, et al. Allogeneic transplant and CAR-T therapy after autologous transplant failure in DLBCL: a noncomparative cohort analysis. Blood Adv, 2022, 6(2): 486-494.
14.	Sigmund AM, Denlinger N, Huang Y, et al. Assessment of salvage regimens post-chimeric antigen receptor t cell therapy for patients with diffuse large B cell lymphoma. Transplant Cell Ther, 2022, 28(6): 342. e1-342. e5.
15.	Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant vs. chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood, 2022, 139(9): 1330-1339.
16.	Wang T, Xu L, Gao L, et al. Chimeric antigen receptor T-cell therapy combined with autologous stem cell transplantation improved progression-free survival of relapsed or refractory diffuse large B-cell lymphoma patients: a single-center, retrospective, cohort study. Hematol Oncol, 2022, 40(4): 637-644.
17.	Oki Y, Kelly KR, Flinn I, et al. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica, 2017, 102(11): 1923-1930.
18.	Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv, 2022, 6(2): 533-543.
19.	Avivi I, Perry C, Segman Y, et al. Polatuzumab-based regimen or CAR T cell for patients with refractory/relapsed DLBCL-a matched cohort analysis. Ann Hematol, 2022, 101(4): 755-762.
20.	Kamdar M, Solomon SR, Arnason J, 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. Lancet, 2022, 399(10343): 2294-2308.
21.	Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med, 2022, 386(7): 640-654.
22.	Locke FL, Miklos DB, Jacobson C, et al. Primary analysis of ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (Axi-Cel) versus standard-of-care therapy in patients with relapsed/refractory large B-cell lymphoma. Blood, 2021, 138 (Suppl 1): 2.
23.	Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol, 2010, 28(27): 4184-4190.
24.	Visani G, Guidi S, Scalzulli P, et al. Benda-BEAM high-dose therapy prior to Auto-SCT is effective in resistant/relapsed DLBCL. Biol Blood Marrow Transplant, 2016, 22(3): S38.
25.	Li N, Zheng B, Cai H, et al. Cost-effectiveness analysis of axicabtagene ciloleucel vs. salvage chemotherapy for relapsed or refractory adult diffuse large B-cell lymphoma in China. Support Care Cancer, 2022, 30(7): 6113-6121.
26.	Aribi M, Mesli N, Remla N, et al. Gemcitabine and treatment of diffuse large B-cell lymphoma in relapsed or refractory elderly patients: a prospective randomized trial in Algeria. J Cancer Res Ther, 2010, 6(1): 41-46.
27.	Fayad L, Ansell SM, Advani R, et al. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leuk Lymphoma, 2015, 56(9): 2569-2578.
28.	van Imhoff GW, McMillan A, Matasar MJ, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD Study. J Clin Oncol, 2017, 35(5): 544-551.
29.	Avilés A, Nambo MJ, Castañeda C, et al. Rituximab and escalated chemotherapy in elderly patients with aggressive diffuse large-cell lymphoma: a controlled clinical trial. Cancer Biother Radiopharm, 2007, 22(2): 194-199.
30.	Avilés A, Nambo MJ, Neri N, et al. Dose dense (CEOP-14) vs. dose dense and rituximab (CEOP-14 +R) in high-risk diffuse large cell lymphoma. Med Oncol, 2007, 24(1): 85-89.
31.	Shimoni A, Avivi I, Rowe JM, et al. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer, 2012, 118(19): 4706-4714.

1. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev, 2019, 10(10): ED000142.
2. 王浩, 唐晓宇, 王和平, 等. ROBINS-I: 评估非随机干预性研究偏倚风险的新工具. 中国循证心血管医学杂志, 2018, 10(7): 789-793.
3. Mey UJ, Olivieri A, Orlopp KS, et al. DHAP in combination with rituximab vs. DHAP alone as salvage treatment for patients with relapsed or refractory diffuse large B-cell lymphoma: a matched-pair analysis. Leuk Lymphoma, 2006, 47(12): 2558-2566.
4. Avilés A, Neri N, Huerta-Guzmán J, et al. ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk, 2010, 10(2): 125-128.
5. Assouline SE, Nielsen TH, Yu S, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood, 2016, 128(2): 185-194.
6. Vellenga E, van Putten WL, van 't Veer MB, et al. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood, 2008, 111(2): 537-543.
7. 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. N Engl J Med, 1995, 333(23): 1540-1545.
8. Morschhauser F, Illidge T, Huglo D, et al. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood, 2007, 110(1): 54-58.
9. Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood, 2004, 103(10): 3684-3688.
10. Sieniawski M, Staak O, Glossmann JP, et al. Rituximab added to an intensified salvage chemotherapy program followed by autologous stem cell transplantation improved the outcome in relapsed and refractory aggressive non-Hodgkin lymphoma. Ann Hematol, 2007, 86(2): 107-115.
11. 张慕晨, 钱樱, 郝杰, 等. 二线方案治疗98例复发难治弥漫大B细胞淋巴瘤的疗效及预后分析. 中华血液学杂志, 2017, 38(6): 511-516.
12. Czuczman MS, Trněný M, Davies A, et al. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res, 2017, 23(15): 4127-4137.
13. Hamadani M, Gopal AK, Pasquini M, et al. Allogeneic transplant and CAR-T therapy after autologous transplant failure in DLBCL: a noncomparative cohort analysis. Blood Adv, 2022, 6(2): 486-494.
14. Sigmund AM, Denlinger N, Huang Y, et al. Assessment of salvage regimens post-chimeric antigen receptor t cell therapy for patients with diffuse large B cell lymphoma. Transplant Cell Ther, 2022, 28(6): 342. e1-342. e5.
15. Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant vs. chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood, 2022, 139(9): 1330-1339.
16. Wang T, Xu L, Gao L, et al. Chimeric antigen receptor T-cell therapy combined with autologous stem cell transplantation improved progression-free survival of relapsed or refractory diffuse large B-cell lymphoma patients: a single-center, retrospective, cohort study. Hematol Oncol, 2022, 40(4): 637-644.
17. Oki Y, Kelly KR, Flinn I, et al. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica, 2017, 102(11): 1923-1930.
18. Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv, 2022, 6(2): 533-543.
19. Avivi I, Perry C, Segman Y, et al. Polatuzumab-based regimen or CAR T cell for patients with refractory/relapsed DLBCL-a matched cohort analysis. Ann Hematol, 2022, 101(4): 755-762.
20. Kamdar M, Solomon SR, Arnason J, 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. Lancet, 2022, 399(10343): 2294-2308.
21. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med, 2022, 386(7): 640-654.
22. Locke FL, Miklos DB, Jacobson C, et al. Primary analysis of ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (Axi-Cel) versus standard-of-care therapy in patients with relapsed/refractory large B-cell lymphoma. Blood, 2021, 138 (Suppl 1): 2.
23. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol, 2010, 28(27): 4184-4190.
24. Visani G, Guidi S, Scalzulli P, et al. Benda-BEAM high-dose therapy prior to Auto-SCT is effective in resistant/relapsed DLBCL. Biol Blood Marrow Transplant, 2016, 22(3): S38.
25. Li N, Zheng B, Cai H, et al. Cost-effectiveness analysis of axicabtagene ciloleucel vs. salvage chemotherapy for relapsed or refractory adult diffuse large B-cell lymphoma in China. Support Care Cancer, 2022, 30(7): 6113-6121.
26. Aribi M, Mesli N, Remla N, et al. Gemcitabine and treatment of diffuse large B-cell lymphoma in relapsed or refractory elderly patients: a prospective randomized trial in Algeria. J Cancer Res Ther, 2010, 6(1): 41-46.
27. Fayad L, Ansell SM, Advani R, et al. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leuk Lymphoma, 2015, 56(9): 2569-2578.
28. van Imhoff GW, McMillan A, Matasar MJ, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD Study. J Clin Oncol, 2017, 35(5): 544-551.
29. Avilés A, Nambo MJ, Castañeda C, et al. Rituximab and escalated chemotherapy in elderly patients with aggressive diffuse large-cell lymphoma: a controlled clinical trial. Cancer Biother Radiopharm, 2007, 22(2): 194-199.
30. Avilés A, Nambo MJ, Neri N, et al. Dose dense (CEOP-14) vs. dose dense and rituximab (CEOP-14 +R) in high-risk diffuse large cell lymphoma. Med Oncol, 2007, 24(1): 85-89.
31. Shimoni A, Avivi I, Rowe JM, et al. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer, 2012, 118(19): 4706-4714.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of salvage therapeutic regimens for the relapsed/refractory diffuse large B cell lymphoma: a network meta-analysis

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