High-dose Chemotherapy Combined with Autologous Hematopoietic Stem Cell Transplantation as Frontline Therapy for Intermediate/High-risk Diffuse Large B Cell Lymphoma

Abstract

The role of autologous hematopoietic stem cell transplantation (auto-HSCT) following high-dose chemotherapy has been validated and accepted as a standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL). However, its clinical efficacy as frontline therapy remains to be elucidated. This study aimed to examine the feasibility of frontline auto-HSCT for newly diagnosed intermediate/high-risk DLBCL patients. We retrospectively reviewed the data of 223 patients treated with frontline auto-HSCT or chemotherapy alone (year 2008–2014) from four hospitals. The median follow-up time was 29.4 months. Between the two treatment arms among the intermediate/high-risk DLBCL patients, the 3-year overall survival (OS) and progression-free survival (PFS) rates of patients given frontline auto-HSCT were 87.6% and 81.9%, respectively, and the chemotherapy-alone group showed 3-year OS and PFS rates of 64.9% and 59.59%, respectively. Compared with the chemotherapy-alone group, the frontline auto-HSCT could eliminate the adverse impact of non-germinal center B-cell (GCB) type. In addition, in the frontline auto-HSCT group, patients who achieved complete response (CR) at auto-HSCT had a longer survival time than those who did not achieve CR. Our results suggested that frontline auto-HSCT could improve the prognosis of intermediate/high-risk DLBCL patients.

Keywords

diffuse large B-cell lymphoma / intermediate/high risk / autologous hematopoietic stem cell transplantation / frontline therapy

References

[1] Al-HamadaniM, HabermannTM, CerhanJR, et al.. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol, 2015, 90(9): 790-795

[2] ArmitageJO, WeisenburgerDD. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol, 1998, 16(8): 2780-2795

[3] CoiffierB, LepageE, BriereJ, et al.. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med, 2002, 346(4): 235-242

[4] FeugierP, Van HoofA, SebbanC, et al.. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol, 2005, 23(18): 4117-4126

[5] PfreundschuhM, TrumperL, OsterborgA, et al.. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol, 2006, 7(5): 379-391

[6] CoiffierB, ThieblemontC, Van Den NesteE, 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(12): 2040-2045

[7] PfreundschuhM, KuhntE, TrumperL, et al.. CHOPlike chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol, 2011, 12(11): 1013-1022

[8] DelarueR, TillyH, MounierN, et al.. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol, 2013, 14(6): 525-533

[9] SehnLH, BerryB, ChhanabhaiM, et al.. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood, 2007, 109(5): 1857-1861

[10] YoonJH, KimJW, JeonYW, et al.. Role of frontline autologous stem cell transplantation in young, high-risk diffuse large B-cell lymphoma patients. Korean J Intern Med, 2015, 30(3): 362-371

[11] StiffPJ, UngerJM, CookJR, et al.. Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med, 2013, 369(18): 1681-1690

[12] CortelazzoS, TarellaC, GianniAM, et al.. Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas. J Clin Oncol, 2016, 34(33): 4015-4022

[13] ChiappellaA, MartelliM, AngelucciE, et al.. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol, 2017, 18(8): 1076-1088

[14] Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program, 2009:523–531

[15] JuweidME, StroobantsS, HoekstraOS, et al.. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol, 2007, 25(5): 571-578

[16] GaoL, ZhangY, HuB, et al.. Phase II Multicenter, Randomized, Double-Blind Controlled Study of Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cells in the Prophylaxis of Chronic Graft-Versus-Host Disease After HLA-Haploidentical Stem-Cell Transplantation. J Clin Oncol, 2016, 34(24): 2843-2850

[17] LiuY, RaoJ, LiJ, et al.. Tandem autologous hematopoietic stem cell transplantation for treatment of adult T-cell lymphoblastic lymphoma: a multiple center prospective study in China. Haematologica, 2021, 106(1): 163-172

[18] CostaLJ, FeldmanAL, MicallefIN, et al.. Germinal center B (GCB) and non-GCB cell-like diffuse large B cell lymphomas have similar outcomes following autologous haematopoietic stem cell transplantation. Br J Haematol, 2008, 142(3): 404-412

[19] RosenwaldA, WrightG, ChanWC, et al.. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med, 2002, 346(25): 1937-1947

[20] CampRL, Dolled-FilhartM, RimmDL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res, 2004, 10(21): 7252-7259

[21] BlayJ, GomezF, SebbanC, et al.. The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood, 1998, 92(10): 3562-3568

[22] PhilipT, GuglielmiC, HagenbeekA, 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

[23] HaiounC, LepageE, GisselbrechtC, et al.. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol—a groupe d’Etude des lymphomes de l’Adulte study. J Clin Oncol, 2000, 18(16): 3025-3030

[24] SantiniG, SalvagnoL, LeoniP, et al.. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin’s lymphoma: results of a prospective randomized trial by the non-Hodgkin’s Lymphoma Cooperative Study Group. J Clin Oncol, 1998, 16(8): 2796-2802

[25] MilpiedN, DeconinckE, GaillardF, et al.. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med, 2004, 350(13): 1287-1295

[26] GrebA, BohliusJ, SchieferD, et al.. High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults. Cochrane Database Syst Rev, 2008, 1: CD004024

[27] StrehlJ, MeyU, GlasmacherA, et al.. High-dose chemotherapy followed by autologous stem cell transplantation as first-line therapy in aggressive non-Hodgkin’s lymphoma: a meta-analysis. Haematologica, 2003, 88(11): 1304-1315

[28] VitoloU, ChiappellaA, AngelucciE, et al.. Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study. Haematologica, 2009, 94(9): 1250-1258

[29] StiffPJ, UngerJM, CookJR, et al.. Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med, 2013, 369(18): 1681-1690

[30] ZhaoY, WangH, JinS, et al.. Prognostic analysis of DLBCL patients and the role of upfront ASCT in high-intermediate and high-risk patients. Oncotarget, 2017, 8(42): 73168-73176

[31] CortelazzoS, TarellaC, GianniAM, et al.. Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas. J Clin Oncol, 2016, 34(33): 4015-4022

[32] EpperlaN, HamadaniM, ReljicT, et al.. Upfront autologous hematopoietic stem cell transplantation consolidation for patients with aggressive B-cell lymphomas in first remission in the rituximab era: A systematic review and meta-analysis. Cancer, 2019, 125(24): 4417-4425

[33] GisselbrechtC, GlassB, MounierN, 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

[34] MartinA, CondeE, ArnanM, et al.. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study, Haematologica, 2008, 93(12): 1829-1836

[35] FenskeTS, HariPN, CarrerasJ, et al.. Impact of pretransplant rituximab on survival after autologous hematopoietic stem cell transplantation for diffuse large B cell lymphoma. Biol Blood Marrow Transplant, 2009, 15(11): 1455-1464

[36] MounierN, CanalsC, GisselbrechtC, et al.. Highdose 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(5): 788-793

[37] HamlinPA, ZelenetzAD, KewalramaniT, et al.. Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma. Blood, 2003, 102(6): 1989-1996