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DA-EPOCH-R improves the outcome over that of R-CHOP regimen for DLBCL patients below 60 years, GCB phenotype, and those with high-risk IPI, but not for double expressor lymphoma

  • Original Article – Cancer Research
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Abstract

Purpose

This study was to compare DA-EPOCH-R and R-CHOP regimen as first-line therapy in diffuse large B cell lymphoma (DLBCL) patients, retrospectively.

Methods

A total of 252 cases treated with R-CHOP and 146 cases who received DA-EPOCH-R were enrolled into this study.

Results

Overall, 162 (64.3%) and 105 patients (71.9%) achieved complete remission, 43 (17.1%) and 14 patients (9.6%) achieved partial remission following R-CHOP and DA-EPOCH-R regimen, respectively. After a median follow-up of 48 months, better progression-free survival (PFS) was seen in DA-EPOCH-R group, but no better overall survival (OS) was found in patients treated with DA-EPOCH-R compared to R-CHOP (P = 0.015 for PFS, P = 0.19 for OS). However, subgroup analysis according to cell of origin, international prognostic index (IPI), and age showed DA-EPOCH-R resulted in significantly better PFS and OS than R-CHOP regimen in patients with germinal center B-cell-like (GCB) phenotype (P = 0.002 for PFS, P = 0.007 for OS), high IPI (P = 0.002 for PFS; P = 0.03 for OS), and with a younger age (P = 0.002 for PFS, P = 0.045 for OS). We also compared two regimens in patients with double expressor lymphoma (DEL). The prognosis of DEL patients was significantly worse than non-DEL patients (P < 0.001 for PFS, P < 0.001 for OS), but DA-EPOCH-R regimen may not overcome the poor prognosis (P = 0.47 for PFS, P = 0.79 for OS).

Conclusion

GCB DLBCL, younger patients, and high-risk patients, but not DEL patients, may benefit from continuous-infusion DA-EPOCH-R regimen.

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References

  • Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, Kluin PM (2011) Double-hit B-cell lymphomas. Blood 117:2319–2331

    Article  CAS  PubMed  Google Scholar 

  • Bai M, Agnantis NJ, Skyrlas A, Tsanou E, Kamina S, Galani V, Kanavaros P (2003) Increased expression of the bcl6 and CD10 proteins is associated with increased apoptosis and proliferation in diffuse large B-cell lymphomas. Mod Pathol 16:471–480

    Article  CAS  PubMed  Google Scholar 

  • Borthakur G, Dawson MA, Stein EM, Karadimitris A, Huntly BJP, Dickinson MJ, Chaidos A, Horner T, Brennan J, Baron J, Kremer BE, Dhar A (2016) A phase I/II openlabel, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in subjects with relapsed, refractory hematologic malignancies. Blood 128:5223

    Google Scholar 

  • Chen AI, Leonard JT, Okada CY, Gay ND, Chansky K, Fan G, Dunlap JB, Raess PW, Braziel RM, Stentz A, Maziarz RT (2017) Outcomes of DA-EPOCH-R induction plus autologous transplant consolidation for double hit lymphoma. Leuk Lymphoma 3:1–6

    Google Scholar 

  • Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586

    Article  PubMed  Google Scholar 

  • Chihara D, Westin JR, Oki Y, Ahmed MA, Do B, Fayad LE, Hagemeister FB, Romaguera JE, Fanale MA, Lee HJ, Turturro F, Samaniego F, Neelapu SS, Rodriguez MA, Fowler NH, Wang M, Davis RE, Nastoupil LJ (2016) Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma. Cancer 122:3145–3151

    Article  CAS  PubMed  Google Scholar 

  • Chiu KC, Fine M, Ikle D, Slovak ML, Arber DA (2003) Telomerase activity and proliferation index in aggressive mature B-cell lymphoma: comparison to germinal center phenotypic markers. Hum Pathol 34:1259–1264

    Article  CAS  PubMed  Google Scholar 

  • Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Ferme C, Tilly H (2010) 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 116:2040–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis RE, Brown KD, Siebenlist U, Staudt LM (2001) Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194:1861–1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drewinko B, Barlogie B (1976) Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP-16-213. Cancer Treat Rep 60:1295–1306

    CAS  PubMed  Google Scholar 

  • Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, Wilson WH (2009) Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113:6069–6076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunleavy K, Pittaluga S, Shovlin M, Steinberg SM, Cole D, Grant C, Widemann B, Staudt LM, Jaffe ES, Little RF, Wilson WH (2013) Low-intensity therapy in adults with Burkitt’s lymphoma. N Engl J Med 369:1915–1925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, Nielsen O, Gadeberg OV, Mourits-Andersen T, Frederiksen M, Pedersen LM, Moller MB (2012) Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:3460–3467

    Article  CAS  PubMed  Google Scholar 

  • Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Müller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282

    Article  CAS  PubMed  Google Scholar 

  • Hansen MM, Bloomfield CD, Jorgensen J, Ersboll J, Pedersen-Bjergaard J, Blom J, Nissen NI (1980) VP-16-213 in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone in the treatment of non-Hodgkin’s lymphomas. Cancer Treat Rep 64:1135–1137

    CAS  PubMed  Google Scholar 

  • Hasselblom S, Ridell B, Sigurdardottir M, Hansson U, Nilsson-Ehle H, Andersson PO (2008) Low rather than high Ki-67 protein expression is an adverse prognostic factor in diffuse large B-cell lymphoma. Leuk Lymphoma 49:1501–1509

    Article  CAS  PubMed  Google Scholar 

  • Herrera AF, Mei M, Low L, Kim HT, Griffin GK, Song JY, Merryman RW, Bedell V, Pak C, Sun H, Paris T, Stiller T, Brown JR, Budde LE, Chan WC, Chen R, Davids MS, Freedman AS, Fisher DC, Jacobsen ED, Jacobson CA, LaCasce AS, Murata-Collins J, Nademanee AP, Palmer JM, Pihan GA, Pillai R, Popplewell L, Siddiqi T, Sohani AR, Zain J, Rosen ST, Kwak LW, Weinstock DM, Forman SJ, Weisenburger DD, Kim Y, Rodig SJ, Krishnan A, Armand P (2017) Relapsed or refractory double-expressor and double-hit lymphomas have inferior progression-free survival after autologous stem-cell transplantation. J Clin Oncol 35:24–31

    Article  CAS  PubMed  Google Scholar 

  • Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A (2015) Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol 170:504–514

    Article  PubMed  Google Scholar 

  • Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, Liu WM, Visco C, Li Y, Miranda RN, Montes-Moreno S, Dybkaer K, Chiu A, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Choi WW, Zhao X, van Krieken JH, Huang Q, Huh J, Ai W, Ponzoni M, Ferreri AJ, Zhou F, Slack GW, Gascoyne RD, Tu M, Variakojis D, Chen W, Go RS, Piris MA, Moller MB, Medeiros LJ, Young KH (2013) MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 121:4021–4031, 4250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, Dyer MJ, Siebert R, Kuruvilla J, Klasa R, Connors JM, Gascoyne RD, Horsman DE (2009) Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 114:2273–2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, Scott DW, Tan KL, Steidl C, Sehn LH, Chan WC, Iqbal J, Meyer PN, Lenz G, Wright G, Rimsza LM, Valentino C, Brunhoeber P, Grogan TM, Braziel RM, Cook JR, Tubbs RR, Weisenburger DD, Campo E, Rosenwald A, Ott G, Delabie J, Holcroft C, Jaffe ES, Staudt LM, Gascoyne RD (2012) Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:3452–3459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson-Farley N, Veliz J, Bhagavathi S, Bertino JR (2015) ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in “double hit” lymphoma cells. Leuk Lymphoma 56:2146–2152

    Article  CAS  PubMed  Google Scholar 

  • Kawashima I, Inamoto Y, Maeshima AM, Nomoto J, Tajima K, Honda T, Shichijo T, Kawajiri A, Takemura T, Onishi A, Ito A, Tanaka T, Fuji S, Kurosawa S, Kim SW, Maruyama D, Tobinai K, Kobayashi Y, Fukuda T (2018) Double-expressor lymphoma is associated with poor outcomes after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 24:294–300

    Article  PubMed  Google Scholar 

  • Lai GM, Chen YN, Mickley LA, Fojo AT, Bates SE (1991) P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer 49:696–703

    Article  CAS  PubMed  Google Scholar 

  • Lam LT, Davis RE, Pierce J, Hepperle M, Xu Y, Hottelet M, Nong Y, Wen D, Adams J, Dang L, Staudt LM (2005) Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin Cancer Res 11:28–40

    Article  CAS  PubMed  Google Scholar 

  • Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: cotswolds meeting. J Clin Oncol 7:1630–1636

    Article  CAS  PubMed  Google Scholar 

  • Meignan M, Gallamini A, Haioun C, Barrington S, Itti E, Luminari S, Polliack A (2015) Report on the 5th International Workshop on positron emission tomography in lymphoma held in Menton, France, 19–20 September 2014. Leuk Lymphoma 56:1229–1232

    Article  PubMed  Google Scholar 

  • Miller TP, Grogan TM, Dahlberg S, Spier CM, Braziel RM, Banks PM, Foucar K, Kjeldsberg CR, Levy N, Nathwani BN (1994) Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin’s lymphomas: a prospective Southwest Oncology Group trial. Blood 83:1460–1466

    CAS  PubMed  Google Scholar 

  • Offner F, Samoilova O, Osmanov E, Eom HS, Topp MS, Raposo J, Pavlov V, Ricci D, Chaturvedi S, Zhu E, van de Velde H, Enny C, Rizo A, Ferhanoglu B (2015) Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood 126:1893–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, Ahmed M, Rodriguez MA, Hagemeister FB, Fowler N, Wang M, Fanale MA, Nastoupil L, Samaniego F, Lee HJ, Dabaja BS, Pinnix CC, Medeiros LJ, Nieto Y, Khouri I, Kwak LW, Turturro F, Romaguera JE, Fayad LE, Westin JR (2014) Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol 166:891–901

    Article  CAS  PubMed  Google Scholar 

  • Petrich AM, Gandhi M, Jovanovic B, Castillo JJ, Rajguru S, Yang DT, Shah KA, Whyman JD, Lansigan F, Hernandez-Ilizaliturri FJ, Lee LX, Barta SK, Melinamani S, Karmali R, Adeimy C, Smith S, Dalal N, Nabhan C, Peace D, Vose J, Evens AM, Shah N, Fenske TS, Zelenetz AD, Landsburg DJ, Howlett C, Mato A, Jaglal M, Chavez JC, Tsai JP, Reddy N, Li S, Handler C, Flowers CR, Cohen JB, Blum KA, Song K, Sun HL, Press O, Cassaday R, Jaso J, Medeiros LJ, Sohani AR, Abramson JS (2014) Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood 124:2354–2361

    Article  CAS  PubMed  Google Scholar 

  • Pfeifer M, Grau M, Lenze D, Wenzel SS, Wolf A, Wollert-Wulf B, Dietze K, Nogai H, Storek B, Madle H, Dörken B, Janz M, Dirnhofer S, Lenz P, Hummel M, Tzankov A, Lenz G (2013) PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA 110:12420–12425

    Article  PubMed  PubMed Central  Google Scholar 

  • Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, Kridel R, Barry GS, Hother C, Abrisqueta P, Boyle M, Meissner B, Telenius A, Savage KJ, Sehn LH, Slack GW, Steidl C, Staudt LM, Connors JM, Rimsza LM, Gascoyne RD (2015) Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol 33:2848–2856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Şen Türk N, Özsan N, Caner V, Karagenç N, Düzcan F, Düzcan E, Hekimgil M (2011) Determination of apoptosis, proliferation status and O6-methylguanine DNA methyltransferase methylation profiles in different immunophenotypic profiles of diffuse large B-cell lymphoma. Turk J Haematol 28:15–26

    PubMed  Google Scholar 

  • Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM (2000) BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13:199–212

    Article  CAS  PubMed  Google Scholar 

  • Snak Y, Indrawati, Widayati K, Arfian N, Anggorowati N (2018) Molecular subtypes, apoptosis and proliferation status in indonesian diffuse large B-cell lymphoma cases. Asian Pac J Cancer Prev 19:185–191

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swerdlow S, Campo E, Lee Harris N, Jaffe E, Pileri S, Stein H, Thiele J, Vardiman J (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, 4 edn. WHO Press, Lyon

    Google Scholar 

  • Varga C, Holcroft C, Kezouh A, Bucatel S, Johnson N, Petrogiannis-Haliotis T, Assouline S (2014) Comparison of outcomes among patients aged 80 and over and younger patients with diffuse large B-cell lymphoma: a population based study. Leuk Lymphoma 55:533–537

    Article  CAS  PubMed  Google Scholar 

  • Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, Kohler DR, Jaffe ES, Herdt J, Cheson BD (1993) EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol 11:1573–1582

    Article  CAS  PubMed  Google Scholar 

  • Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F (2002) Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood 99:2685–2693

    Article  CAS  PubMed  Google Scholar 

  • Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE (2008) Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 26:2717–2724

    Article  CAS  PubMed  Google Scholar 

  • Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED (2012) A cancer and leukemia group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97:758–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yalowich JC (1987) Effects of microtubule inhibitors on etoposide accumulation and DNA damage in human K562 cells in vitro. Can Res 47:1010–1015

    CAS  Google Scholar 

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Funding

This study was supported by National Natural Science Foundation of China (81370657, 81470328, 81600130, 81770166, 81720108002), Jiangsu Province’s Medical Elite Programme (ZDRCA2016022), Project of National Key Clinical Specialty, National Science and Technology Pillar Program (2014BAI09B12), Jiangsu Provincial Special Program of Medical Science (BL2014086 and BE2017751) and National Science and Technology Major Project (2017ZX09304032).

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Correspondence to Wei Xu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

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Informed coansent was obtained from all individual participants included in the study.

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Zhang, XY., Liang, JH., Wang, L. et al. DA-EPOCH-R improves the outcome over that of R-CHOP regimen for DLBCL patients below 60 years, GCB phenotype, and those with high-risk IPI, but not for double expressor lymphoma. J Cancer Res Clin Oncol 145, 117–127 (2019). https://doi.org/10.1007/s00432-018-2771-9

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