Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lymphoma

Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study

Abstract

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D 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: 1540–1545.

    Article  CAS  PubMed  Google Scholar 

  2. Gisselbrecht C . Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Hematology Am Soc Hematol Educ Program 2012; 2012: 410–416.

    PubMed  Google Scholar 

  3. Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH 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: 537–543.

    Article  CAS  PubMed  Google Scholar 

  4. Karlin L, Coiffier B . Improving survival and preventing recurrence of diffuse large B-cell lymphoma in younger patients: current strategies and future directions. Onco Targets Ther 2013; 6: 289–296.

    PubMed  PubMed Central  Google Scholar 

  5. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S et al. 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. Blood 2010; 116: 2040–2045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gunnellini M, Emili R, Coaccioli S, Liberati AM . The role of autologous stem cell transplantation in the treatment of diffuse large B-cell lymphoma. Adv Hematol 2012; 2012: 195484.

    PubMed  PubMed Central  Google Scholar 

  7. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–4190.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 2012; 30: 4462–4469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hamadani M, Hari PN, Zhang Y, Carreras J, Akpek G, Aljurf MD et al. Early failure of frontline rituximab-containing chemo-immunotherapy in diffuse large B cell lymphoma does not predict futility of autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014; 20: 1729–1736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mounier N, Canals C, Gisselbrecht C, Cornelissen J, Foa R, Conde E et al. High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era: an analysis based on data from the European Blood and Marrow Transplantation Registry. Biol Blood Marrow Transplant 2012; 18: 788–793.

    Article  PubMed  Google Scholar 

  11. Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT et al. 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. J Clin Oncol 2014; 32: 3490–3496.

    Article  CAS  PubMed  Google Scholar 

  12. Van Den Neste E, Gisselbrecht C, Schmitz N, Mounier N, Gill DS, FMedSci DL et al. Diffuse large B-cell lymphoma (DLBCL) patients failing second-line R-DHAP or R-ICE chemotherapy included in the Coral Study. Blood 2013; 122: 764.

    Google Scholar 

  13. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244.

    Article  CAS  PubMed  Google Scholar 

  14. Thieblemont C, Briere J, Mounier N, Voelker HU, Cuccuini W, Hirchaud E et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol 2011; 29: 4079–4087.

    Article  PubMed  Google Scholar 

  15. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103: 275–282.

    Article  CAS  PubMed  Google Scholar 

  16. Nagle SJ, Woo K, Schuster SJ, Nasta SD, Stadtmauer E, Mick R et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol 2013; 88: 890–894.

    Article  CAS  PubMed  Google Scholar 

  17. Hamadani M, Hari PN, Zhang Y, Carreras J, Akpek G, Aljurf MD et al. Early failure of frontline rituximab-containing chemo-immunotherapy in diffuse large B cell lymphoma does not predict futility of autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014; 20: 1729–1736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gisselbrecht C . Futility of relapsed diffuse large B cell lymphoma transplantation? Biol Blood Marrow Transplant 2014; 20: 1667–1669.

    Article  PubMed  Google Scholar 

  19. Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M et al. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol 2014; 15: 757–766.

    Article  CAS  PubMed  Google Scholar 

  20. Robinson SP, Goldstone AH, Mackinnon S, Carella A, Russell N, de Elvira CR et al. Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 2002; 100: 4310–4316.

    Article  CAS  PubMed  Google Scholar 

  21. Chevallier P, Labopin M, Milpied N, Bilger K, Socie G, Yakoub-Agha I et al. Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). Bone Marrow Transplant 2014; 49: 361–365.

    Article  CAS  PubMed  Google Scholar 

  22. Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS et al. Impact of pretransplantation conditioning regimens on outcomes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B cell lymphoma and grade III follicular lymphoma. Biol Blood Marrow Transplant 2013; 19: 746–753.

    Article  PubMed  PubMed Central  Google Scholar 

  23. van Kampen RJ, Canals C, Schouten HC, Nagler A, Thomson KJ, Vernant JP 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 Clin Oncol 2011; 29: 1342–1348.

    Article  PubMed  Google Scholar 

  24. Elstrom RL, Martin P, Ostrow K, Barrientos J, Chadburn A, Furman R et al. Response to second-line therapy defines the potential for cure in patients with recurrent diffuse large B-cell lymphoma: implications for the development of novel therapeutic strategies. Clin Lymphoma Myeloma Leuk 2010; 10: 192–196.

    Article  CAS  PubMed  Google Scholar 

  25. Seshadri T, Stakiw J, Pintilie M, Keating A, Crump M, Kuruvilla J . Utility of subsequent conventional dose chemotherapy in relapsed/refractory transplant-eligible patients with diffuse large B-cell lymphoma failing platinum-based salvage chemotherapy. Hematology 2008; 13: 261–266.

    Article  CAS  PubMed  Google Scholar 

  26. Simpson L, Ansell SM, Colgan JP, Habermann TM, Inwards DJ, Ristow KM et al. Effectiveness of second line salvage chemotherapy with ifosfamide, carboplatin, and etoposide in patients with relapsed diffuse large B-cell lymphoma not responding to cis-platinum, cytosine arabinoside, and dexamethasone. Leuk Lymphoma 2007; 48: 1332–1337.

    Article  CAS  PubMed  Google Scholar 

  27. Ardeshna KM, Kakouros N, Qian W, Powell MG, Saini N, D'Sa S et al. Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens. Br J Haematol 2005; 130: 363–372.

    Article  CAS  PubMed  Google Scholar 

  28. Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, Climent F, Gonzalez-Barca E, Mercadal S et al. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica 2013; 98: 1554–1562.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gisselbrecht C . Should we replace dexamethasone, cytarabine, and cisplatin for relapsed lymphoma? J Clin Oncol 2014; 32: 3472–3473.

    Article  CAS  PubMed  Google Scholar 

  30. Morschhauser FA, Cartron G, Thieblemont C, Solal-Celigny P, Haioun C, Bouabdallah R et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 2013; 31: 2912–2919.

    Article  CAS  PubMed  Google Scholar 

  31. Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G et al. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood 2013; 122: 499–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol 2014; 15: 1019–1026.

    Article  CAS  PubMed  Google Scholar 

  33. Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA 2014; 111: 2349–2354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the LYSARC for coordinating the study; Fabienne Morand, Sami Boussetta, Marion Fournier, Laurence Girard, Clemence Capron and the project leaders from the different countries; the patients and their families; AJE for reviewing the English; Catherine Druon for preparing the manuscript; and all investigators (see Supplementary Materials) and pathologists. This work was supported by research grants from F-Hoffmann La Roche Ltd, LYSARC. Written on behalf of the CORAL (Collaborative trial in Relapsed Aggressive Lymphoma).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Gisselbrecht.

Ethics declarations

Competing interests

CG: Roche—Research Funding. MT: Roche—Honoraria, Research Funding. JR: Roche—Consultancy. OS: Roche—Consultancy, Honoraria, Research Funding. UD: Roche Pharma—Honoraria, Research Funding. CHM: Genentech—Consultancy, Research Funding. BG: Roche—Honoraria, Research Funding. GS: Roche—Honoraria, research funding. The authors declare no conflict of interest.

Additional information

Preliminary results were presented at the 55th ASH 2013 annual meeting (Blood 2013; 122: 764).

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Van Den Neste, E., Schmitz, N., Mounier, N. et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant 51, 51–57 (2016). https://doi.org/10.1038/bmt.2015.213

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.213

This article is cited by

Search

Quick links