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Clinical risk scores do not accurately identify a very high risk population with diffuse large B cell lymphoma—an analysis of 386 Portuguese patients

  • Rita CoutinhoEmail author
  • J. Lobato
  • S. Esteves
  • J. Cabeçadas
  • M. Gomes da Silva
Original Article

Abstract

The identification of high-risk patients deserving alternative first-line treatments to R-CHOP is a research priority in diffuse large B cell lymphoma (DLBCL). Despite the increasing recognition of biological features underlying aggressive behavior, clinical scores remain the basis for prognostic evaluation and treatment stratification in DLBCL. We performed a retrospective analysis of patients with DLBCL uniformly treated with immunochemotherapy with the aim of assessing the discriminative power of the NCCN international prognostic index (IPI) and the GELTAMO-IPI scores in risk group stratification and compared them with the IPI. Additionally, we investigated if bulky disease, gender, beta-2 microglobulin (β2m), body mass index, and B-symptoms have independent prognostic impact. We confirmed the discriminative ability of the three prognostic scores in terms of progression-free survival and overall survival and found that the NCCN-IPI performs better in the identification of a high-risk population compared to the IPI and the GELTAMO scores. In an attempt to improve the prognostic power of the NCCN-IPI we analyzed additional clinical variables. Bulky disease and elevated β2m were found to be independent predictors of prognosis when controlling for the NCCN-IPI risk groups. However, they seem to bring no incremental power to the latter in the identification of poor outcome patients. We support the use of the NCCN-IPI for the clinical identification of high-risk patients in DLBCL. Future studies to unravel the biological heterogeneity within NCCN-IPI groups are needed to improve risk prediction and design targeted therapies for poor prognosis patients.

Keywords

Diffuse large B cell lymphoma GELTAMO-IPI NCCN-IPI Outcome High risk 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Ethics Committee of Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisbon, Portugal.

Supplementary material

277_2019_3676_MOESM1_ESM.docx (16 kb)
ESM 1 (DOCX 15 kb)
277_2019_3676_MOESM2_ESM.docx (13 kb)
ESM 2 (DOCX 12 kb)

References

  1. 1.
    Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127(20):2375–2390CrossRefGoogle Scholar
  2. 2.
    Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511CrossRefGoogle Scholar
  3. 3.
    Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, López-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM, Lymphoma/Leukemia Molecular Profiling Project (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937–1947CrossRefGoogle Scholar
  4. 4.
    Lenz G, Wright GW, Emre NC et al (2008) Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A 105:13520–13525CrossRefGoogle Scholar
  5. 5.
    Schmitz R, Wright GW, Huang DW et al (2018) Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med 378(15):1396–1407CrossRefGoogle Scholar
  6. 6.
    Gisselbrecht C, Glass B, Mournier N et al (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28(27):4184–4190CrossRefGoogle Scholar
  7. 7.
    Crump M, Neelapu SS, Farooq U, van den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L, Boussetta S, Feng L, Maurer MJ, Navale L, Wiezorek J, Go WY, Gisselbrecht C (2017) Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 130(16):1800–1808CrossRefGoogle Scholar
  8. 8.
    Maurer M, Ghesquières H, Jais JP, Witzig TE, Haioun C, Thompson CA, Delarue R, Micallef IN, Peyrade F, Macon WR, Jo Molina T, Ketterer N, Syrbu SI, Fitoussi O, Kurtin PJ, Allmer C, Nicolas-Virelizier E, Slager SL, Habermann TM, Link BK, Salles G, Tilly H, Cerhan JR (2014) Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol 32(10):1066–1073CrossRefGoogle Scholar
  9. 9.
    Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, Kluin PM (2011) Double-hit B-cell lymphomas. Blood 117(8):2319–2331CrossRefGoogle Scholar
  10. 10.
    Ennishi D, Mottok A, Ben-Neriah S, Shulha HP, Farinha P, Chan FC, Meissner B, Boyle M, Hother C, Kridel R, Lai D, Saberi S, Bashashati A, Shah SP, Morin RD, Marra MA, Savage KJ, Sehn LH, Steidl C, Connors JM, Gascoyne RD, Scott DW (2017) Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. Blood 129(20):2760–2770CrossRefGoogle Scholar
  11. 11.
    Sesques P, Johnson NA (2017) Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. Blood 129(3):280–288CrossRefGoogle Scholar
  12. 12.
    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(28):3452–3459CrossRefGoogle Scholar
  13. 13.
    Staiger AM, Ziepert M, Horn H, Scott DW, Barth TFE, Bernd HW, Feller AC, Klapper W, Szczepanowski M, Hummel M, Stein H, Lenze D, Hansmann ML, Hartmann S, Möller P, Cogliatti S, Lenz G, Trümper L, Löffler M, Schmitz N, Pfreundschuh M, Rosenwald A, Ott G, German High-Grade Lymphoma Study Group (2017) Clinical impact of the cell-of-origin classification and the MYC/ BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German high-grade non-Hodgkin’s lymphoma study group. J Clin Oncol 35(22):2515–2526CrossRefGoogle Scholar
  14. 14.
    The International Non-Hodgkin’s Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994CrossRefGoogle Scholar
  15. 15.
    Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM (2007) 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 109:1857–1861CrossRefGoogle Scholar
  16. 16.
    Seo S, Hong JY, Yoon S, Yoo C, Park JH, Lee JB, Park CS, Huh J, Lee Y, Kim KW, Ryu JS, Kim SJ, Kim WS, Yoon DH, Suh C (2016) Prognostic significance of serum beta-2 microglobulin in patients with diffuse large B-cell lymphoma in the rituximab era. Oncotarget 7(47):76934–76943CrossRefGoogle Scholar
  17. 17.
    Melchardt T, Troppan K, Weiss L, Hufnagl C, Neureiter D, Tränkenschuh W, Hopfinger G, Magnes T, Deutsch A, Neumeister P, Hackl H, Greil R, Pichler M, Egle A (2015) A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and beta2-microglobulin. Br J Haematol 168:239–245CrossRefGoogle Scholar
  18. 18.
    Müller C, Murawski N, Wiesen MH et al (2012) The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood 119(14):3276–3284CrossRefGoogle Scholar
  19. 19.
    Hohloch K, Altmann B, Pfreundschuh M, Loeffler M, Schmitz N, Zettl F, Ziepert M, Trümper L (2018) Obesity negatively impacts outcome in elderly female patients with aggressive B-cell lymphomas treated with R-CHOP: results from prospective trials of the German high grade non-Hodgkin’s lymphoma trial group. Br J Haematol 180(2):236–245CrossRefGoogle Scholar
  20. 20.
    Pfreundschuh M, Ho AD, Cavallin-Stahl E, Wolf M, Pettengell R, Vasova I, Belch A, Walewski J, Zinzani PL, Mingrone W, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Corrado C, Scheliga A, Loeffler M, Kuhnt E, MabThera International Trial (MInT) Group (2008) Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol 9:435–444CrossRefGoogle Scholar
  21. 21.
    Zhou Z, Sehn LH, Rademaker AW, Gordon LI, LaCasce AS, Crosby-Thompson A, Vanderplas A, Zelenetz AD, Abel GA, Rodriguez MA, Nademanee A, Kaminski MS, Czuczman MS, Millenson M, Niland J, Gascoyne RD, Connors JM, Friedberg JW, Winter JN (2014) An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123:837–842CrossRefGoogle Scholar
  22. 22.
    Montalbán C, Díaz-López A, Dlouhy I, Rovira J, Lopez-Guillermo A, Alonso S, Martín A, Sancho JM, García O, Sánchez JM, Rodríguez M, Novelli S, Salar A, Gutiérrez A, Rodríguez-Salazar MJ, Bastos M, Domínguez JF, Fernández R, Gonzalez de Villambrosia S, Queizan JA, Córdoba R, de Oña R, López-Hernandez A, Freue JM, Garrote H, López L, Martin-Moreno AM, Rodriguez J, Abraira V, García JF, the GELTAMO-IPI Project Investigators (2017) Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of β2-microglobulin yields a more accurate GELTAMO-IPI. Br J Haematol 176(6):918–928CrossRefGoogle Scholar
  23. 23.
    Bishton MJ, Hughes S, Richardson F, James E, Bessell E, Sovani V, Ganatra R, Haynes AP, McMillan AK, Fox CP (2016) Delineating outcomes of patients with diffuse large b cell lymphoma using the national comprehensive cancer network-international prognostic index and positron emission tomography-defined remission status; a population-based analysis. Br J Haematol 172:246–254CrossRefGoogle Scholar
  24. 24.
    El-Galaly TC, Villa D, Alzahrani M et al (2015) Outcome prediction by extranodal involvement, IPI, R-IPI, and NCCN-IPI in the PET/CT and rituximab era: a Danish-Canadian study of 443 patients with diffuse-large B-cell lymphoma. Am J Hematol 90:1041–1046CrossRefGoogle Scholar
  25. 25.
    Cheson BD, Horning SJ, Coiffier B et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17(4):1244CrossRefGoogle Scholar
  26. 26.
    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, International Harmonization Project on Lymphoma (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25(5):579–586CrossRefGoogle Scholar
  27. 27.
    Harrell FE Jr, Califf RM, Pryor DB et al (1982) Evaluating the yield of medical tests. JAMA 247(18):2543–2546CrossRefGoogle Scholar
  28. 28.
    Uno H, Cai T, Pencina MJ, D'Agostino RB, Wei LJ (2011) On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data. Stat Med 30(10):1105–1117Google Scholar
  29. 29.
    R Core Team (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  30. 30.
    Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, Glass B, Scott DW, Gascoyne RD, Connors JM, Ziepert M, Pfreundschuh M, Loeffler M, Savage KJ (2016) CNS international prognostic index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 34:3150–3156CrossRefGoogle Scholar
  31. 31.
    Gutiérrez-García G, Cardesa-Salzmann T, Climent F et al (2011) Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood 117(18):4836–4843CrossRefGoogle Scholar
  32. 32.
    Coutinho R, Clear AJ, Owen A, Wilson A, Matthews J, Lee A, Alvarez R, da Silva MG, Cabecadas J, Calaminici M, Gribben JG (2013) Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies. Clin Cancer Res 19(24):6686–6695CrossRefGoogle Scholar
  33. 33.
    Biccler J, Eloranta S, Brown N et al (2018) Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI. Cancer Med 7(1):114–122CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of HematologyCentro Hospitalar Universitário do PortoPortoPortugal
  2. 2.Department of HematologyInstituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.LisbonPortugal
  3. 3.Clinical Research UnitInstituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.LisbonPortugal
  4. 4.Department of PathologyInstituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.LisbonPortugal

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