Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis

다국어 초록 (Multilingual Abstract)

Purpose We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis.Materials and Methods R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and chimeric antigen receptor (CAR) T-cell therapy was used as reference treatment.Results Twenty-six ASCT-eligible cohorts from 17 studies comprising 2,924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3,617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval [CI], 0.15 to 0.65) for the CAR T-cell group and 0.34 (95% CI, 0.30 to 0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI, 0.35 to 0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI, 0.37 to 0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment.Conclusion Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.

참고문헌 (Reference)

1 Arnason JE, "Yttrium-90 ibritumomab tiuxetan followed by rituximab maintenance as treatment for patients with diffuse large B-cell lymphoma are not candidates for autologous stem cell transplant" 133 : 347-353, 2015

2 Galanina N, "University of Chicago phase II consortium trial of selumetinib(MEKi)demonstrates low tolerability and efficacy in relapsed DLBCL" 181 : 264-267, 2018

3 Schuster SJ, "Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma" 380 : 45-56, 2019

4 Witzens-Harig M, "The mTOR inhibitor temsirolimus added to rituximab combined with dexamethasone, cytarabine, and cisplatinum(R-DHAP)for the treatment of patients with relapsed or refractory DLBCL : results from the phase-II STORM trial" 5 : e636-, 2021

5 Smith SM, "Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes : the University of Chicago phase II consortium" 28 : 4740-4746, 2010

6 Nowakowski GS, "Tafasitamab plus lenalidomide versus pola-BR, R2, and CAR T : comparing outcomes from RE-MIND2, an observational, retrospective cohort study in relapsed/refractory diffuse large B-cell lymphoma" 138 (138): 183-, 2021

7 Salles G, "Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma(L-MIND) : a multicentre, prospective, single-arm, phase 2 study" 21 : 978-988, 2020

8 Zaja F, "Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma : clinical outcome and correlation with genomic data : a phase 2 study of the Fondazione Italiana Linfomi" 59 : 2904-2910, 2018

9 Lenz G, "Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma" 34 : 2184-2197, 2020

10 Kalakonda N, "Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma(SADAL) : a single-arm, multinational, multicentre, open-label, phase 2 trial" 7 : e511-22, 2020

11 Bishop MR, "Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma" 386 : 629-639, 2022

12 Mussetti A, "Second-line CAR T cells for lymphomas" 399 : 2247-2249, 2022

13 Gisselbrecht C, "Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era" 28 : 4184-4190, 2010

14 Ribrag V, "Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia : results of a phase II study" 102 : 903-909, 2017

15 Younes A, "Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia : a phase 1/2a study" 6 : e67-78, 2019

16 Herrera AF, "Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma" 95 : 18-27, 2020

17 Lugtenburg PJ, "Rituximab-PECC induction followed by(90)Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT : results from a phase II HOVON study" 187 : 347-355, 2019

18 Dang NH, "Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma" 182 : 583-586, 2018

19 Crump M, "Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas : NCIC-CTG LY. 12" 32 : 3490-3496, 2014

20 Kuhnl A, "R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma : results of the UK NRCI phase II randomised LEGEND trial" 99 : 105-112, 2020

21 Sehn LH, "Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL : survival update and new extension cohort data" 6 : 533-543, 2022

22 Morschhauser F, "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)" 6 : e254-65, 2019

23 Sehn LH, "Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma" 38 : 155-165, 2020

24 Pettengell R, "Pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma not eligible for stem cell transplantation : a phase 3, randomized, multicentre trial(PIX306)" 188 : 240-248, 2020

25 Jurczak W, "Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma" 29 : 1266-1272, 2018

26 Sang W, "Phase II trial of co-administration of CD19-and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma" 9 : 5827-5838, 2020

27 Pan J, "Phase I/II study of bendamustine in combination with ofatumumab, carboplatin, etoposide(BOCE)for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma" 62 : 590-597, 2021

28 Major A, "Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas" 107 : 1608-1618, 2022

29 Assouline SE, "Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma" 128 : 185-194, 2016

30 Wilson WH, "Phase 1b/2 study of ibrutinib and lenalidomide with dose-adjusted EPOCH-R in patients with relapsed/refractory diffuse large B-cell lymphoma" 62 : 2094-2106, 2021

31 Barnes JA, "Panobinostat in combination with rituximab in heavily pretreated diffuse large B-cell lymphoma : results of a phase II study" 36 : 633-637, 2018

32 Younes A, "Pan-phosphatidylinositol 3-kinase inhibition with buparlisib in patients with relapsed or refractory non-Hodgkin lymphoma" 102 : 2104-2112, 2017

33 Joshi M, "Outpatient rituximab, ifosfamide, etoposide(R-IE)in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation" 61 : 91-97, 2020

34 Wang M, "Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma : a phase II clinical trial" 27 : 1902-1909, 2013

35 Coyle L, "Open-label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma" 61 : 2103-2112, 2020

36 van Imhoff GW, "Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma : the ORCHARRD study" 35 : 544-551, 2017

37 Matasar MJ, "Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma" 122 : 499-506, 2013

38 Houot R, "Obinutuzumab plus Lenalidomide(GALEN)for the treatment of relapse/refractory aggressive lymphoma : a phase II LYSA study" 33 : 776-780, 2019

39 Ansell SM, "Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation : a single-arm, phase II study" 37 : 481-489, 2019

40 National Comprehensive Cancer Network, "NCCN clinical practice guidelines: B-cell lymphomas V5.2022" National Comprehensive Cancer Network

41 Ohmachi K, "Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma" 31 : 2103-2109, 2013

42 Pettengell R, "Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma : post-hoc analyses from a phase III trial" 174 : 692-699, 2016

43 Stroup DF, "Meta-analysis of observational studies in epidemiology : a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology(MOOSE)group" 283 : 2008-2012, 2000

44 Coiffier B, "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" 116 : 2040-2045, 2010

45 Witzig TE, "Long-term follow-up of chemoimmunotherapy with rituximab, oxaliplatin, cytosine arabinoside, dexamethasone(ROAD)in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma : results of a study of the Mayo Clinic Cancer Center Research Consortium(MCCRC)MC-0485 now known as academic and community cancer research united(ACCRU)" 92 : 1004-1010, 2017

46 Caimi PF, "Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma(LOTIS-2) : a multicentre, open-label, single-arm, phase 2 trial" 22 : 790-800, 2021

47 Kamdar M, "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" 399 : 2294-2308, 2022

48 Abramson JS, "Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas(TRANSCEND NHL 001) : a multicentre seamless design study" 396 : 839-852, 2020

49 Palazon-Carrion N, "Lenalidomide plus R-GDP(R2-GDP)in relapsed/refractory diffuse large B-cell lymphoma : final results of the R2-GDP-GOTEL trial and immune biomarker subanalysis" 28 : 3658-3668, 2022

50 Kang HJ, "Irinotecan plus cisplatin and dexamethasone(ICD)combination chemotherapy for patients with diffuse large B-cell lymphoma previously treated with rituximab plus CHOP" 62 : 299-304, 2008

51 Maziarz RT, "Indirect comparison of tisagenlecleucel and historical treatments for relapsed/refractory diffuse large B-cell lymphoma" 6 : 2536-2547, 2022

52 Graf SA, "Ibrutinib monotherapy in relapsed or refractory, transformed diffuse large B-cell lymphoma" 21 : 176-181, 2021

53 Gyan E, "High response rate and acceptable toxicity of a combination of rituximab, vinorelbine, ifosfamide, mito-xantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse : results of the R-NIMP GOELAMS study" 162 : 240-249, 2013

54 Lopez A, "GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma : a phase II study" 80 : 127-132, 2008

55 Barnes JA, "Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma" 98 : 615-619, 2013

56 Morschhauser F, "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" 110 : 54-58, 2007

57 Sehn LH, "Diffuse large B-cell lymphoma" 384 : 842-858, 2021

58 Fayad L, "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" 56 : 2569-2578, 2015

59 Neelapu SS, "Comparison of 2-year outcomes with CAR T cells(ZUMA-1)vs salvage chemotherapy in refractory large B-cell lymphoma" 5 : 4149-4155, 2021

60 Zinzani PL, "Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma : a phase 2 trial" 11 : 462-466, 2011

61 Hu J, "Combination of decitabine and a modified regimen of cisplatin, cytarabine and dexamethasone : a potential salvage regimen for relapsed or refractory diffuse large B-cell lymphoma after second-line treatment failure" 11 : 687374-, 2021

62 Shargian L, "Chimeric antigen receptor T-cell therapy is superior to standard of care as second-line therapy for large B-cell lymphoma : A systematic review and meta-analysis" 198 : 838-846, 2022

63 Schuster SJ, "Chimeric antigen receptor T cells in refractory B-cell lymphomas" 377 : 2545-2554, 2017

64 Roschewski M, "CAR T-cell therapy for large B-cell lymphoma : who, when, and how?" 386 : 692-696, 2022

65 Murayama K, "Bendamustine plus rituximab in Japanese patients with relapsed or refractory diffuse large B-cell lymphoma" 101 : 979-989, 2022

66 Vacirca JL, "Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma" 93 : 403-409, 2014

67 Locke FL, "Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma" 386 : 640-654, 2022

68 Neelapu SS, "Axicabtagene ciloleucel CAR T-cell the-rapy in refractory large B-cell lymphoma" 377 : 2531-2544, 2017

69 Shadman M, "Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission" 139 : 1330-1339, 2022

70 Burke JM, "An open-label, phase II trial of entospletinib(GS-9973), a selective spleen tyrosine kinase inhibitor, in diffuse large B-cell lymphoma" 18 : e327-31, 2018

71 Coiffier B, "A phase II, single-arm, multicentre study of coltuximab ravtansine(SAR3419)and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma" 173 : 722-730, 2016

72 Hess G, "A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma : final results of the prospective, multicentre GOAL trial" 198 : 482-491, 2022

73 de Vos S, "A phase II study of dacetuzumab(SGN-40)in patients with relapsed diffuse large B-cell lymphoma(DLBCL)and correlative analyses of patient-specific factors" 7 : 44-, 2014

74 Puvvada SD, "A phase II study of belinostat(PXD101)in relapsed and refractory aggressive B-cell lymphomas : SWOG S0520" 57 : 2359-2369, 2016

75 Trneny M, "A phase II multicenter study of the anti-CD19 antibody drug conjugate coltuximab ravtansine(SAR3419)in patients with relapsed or refractory diffuse large B-cell lymphoma previously treated with rituximab-based immunotherapy" 103 : 1351-1358, 2018

76 Czuczman MS, "A phase 2/3 multicenter, randomized, open-lbel study to compare the efficacy and safety of lenalidomide versus investigator’s choice in patients with relapsed or refractory diffuse large B-cell lymphoma" 23 : 4127-4137, 2017

77 Terui Y, "A phase 2 study of polatuzumab vedotin+bendamustine +rituximab in relapsed/refractory diffuse large B-cell lymphoma" 112 : 2845-2854, 2021

78 Batlevi CL, "A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma" 178 : 434-441, 2017

79 Wagner-Johnston ND, "A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma" 56 : 2863-2869, 2015

80 Coiffier B, "A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma" 163 : 334-342, 2013

81 Papadopoulos KP, "A multicenter phase II study of sepantronium bromide(YM155)plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma" 57 : 1848-1855, 2016

82 Teras LR, "2016 US lymphoid malignancy statistics by World Health Organization subtypes" 66 : 443-459, 2016