International Journal of Hematology

, Volume 92, Issue 2, pp 246–254

Follicular lymphoma prognostic factors in the modern era: what is clinically meaningful?

Progress in Hematology Molecular, cellular biology and treatment of B-cell lymphoma

Abstract

Follicular lymphomas (FL) account for 30% of non-Hodgkin’s lymphomas (NHL). Their evolution is heterogeneous. Some patients present with indolent forms undergoing several relapses while in other patients the disease evolves abruptly toward aggressive NHL. This is why accurate prognostic indices are required so that treatment strategies may be optimized for each patient and so that trials may be conducted in groups of patients that are as homogeneous as possible. The Follicular Lymphoma International Prognostic Index (FLIPI) has been designed to separate patients into 3 groups with significantly different hazard ratios for death. Its accuracy has been confirmed in several studies. The FLIPI2 was designed more recently to separate patients with significantly different hazard ratios for progression/relapse in the era of anti-CD20 monoclonal antibody treatments. Gene profile studies have shown that the prognosis of FL is mainly related to the type, number, and activation of immune cells in the microenvironment of lymphomatous follicles. Immunohistochemical studies suggest that macrophages, CD4+ T cells and among them T-regulatory cells (T-regs) and programed death-1 cells (PD-1 cells) play a major role in the outcome of FLs. However, additional confirmatory studies are required due to discrepancies in results. Up to now, these biological study results are more useful for approaching the pathophysiology of FL rather than to be used as prognostic tools in clinical practice.

Keywords

Follicular lymphomas Prognostic factors FLIPI Microenvironment Tumor-associated macrophages T-regulatory cells Programed death-1 T cells 

References

  1. 1.
    Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol. 2005;23:5019–26.CrossRefPubMedGoogle Scholar
  2. 2.
    Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, et al. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006;24:1582–9.CrossRefPubMedGoogle Scholar
  3. 3.
    National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49:2112–35.Google Scholar
  4. 4.
    Decaudin D, Lepage E, Brousse N, Brice P, Harousseau JL, Belhadj K, et al. Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients—a study of the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1999;17:2499–505.PubMedGoogle Scholar
  5. 5.
    Brice P, Bastion Y, Lepage E, Brousse N, Haioun C, Moreau P, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. J Clin Oncol. 1997;15:1110–7.PubMedGoogle Scholar
  6. 6.
    A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987–94.Google Scholar
  7. 7.
    Lopez-Guillermo A, Montserrat E, Bosch F, Terol MJ, Campo E, Rozman C. Applicability of the International Index for Aggressive Lymphomas to patients with low-grade lymphoma. J Clin Oncol. 1994;12:1343–8.PubMedGoogle Scholar
  8. 8.
    Bastion Y, Coiffier B. Is the International Prognostic Index for Aggressive Lymphoma patients useful for follicular lymphoma patients? J Clin Oncol. 1994;12:1340–2.PubMedGoogle Scholar
  9. 9.
    Perea G, Altes A, Montoto S, Lopez-Guillermo A, Domingo-Domenech E, Fernandez-Sevilla A, et al. Prognostic indexes in follicular lymphoma: a comparison of different prognostic systems. Ann Oncol. 2005;16:1508–13.CrossRefPubMedGoogle Scholar
  10. 10.
    Solal-Celigny P. What is the optimal prognostic tool for the assessment of patients with newly diagnosed follicular lymphoma? Leuk Lymphoma. 2007;48:452–3.CrossRefPubMedGoogle Scholar
  11. 11.
    Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular Lymphoma International Prognostic Index. Blood. 2004;104:1258–65.CrossRefPubMedGoogle Scholar
  12. 12.
    Formica V, Norman AR, Cunningham D, Wotherspoon A, Oates J, Chong G. Utility of the Follicular Lymphoma International Prognostic Index and the International Prognostic Index in assessing prognosis and predicting first-line treatment efficacy in follicular lymphoma patients. Acta Haematol. 2009;122:193–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Arcaini L, Colombo N, Passamonti F, Burcheri S, Orlandi E, Brusamolino E, et al. Correlation of the FLIPI score for follicular lymphoma with period of diagnosis and type of treatment. Leuk Res. 2006;30:277–82.CrossRefPubMedGoogle Scholar
  14. 14.
    Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, Hiddemann W. The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood. 2006;108:1504–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579–86.CrossRefPubMedGoogle Scholar
  16. 16.
    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.CrossRefPubMedGoogle Scholar
  17. 17.
    Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27:4555–62.CrossRefPubMedGoogle Scholar
  18. 18.
    Arcaini L, Merli M, Passamonti F, Rizzi S, Ferretti V, Rattotti S, et al. Validation of follicular lymphoma international prognostic index 2 (FLIPI2) score in an independent series of follicular lymphoma patients. Br J Haematol. 2010;149(3):455–7.Google Scholar
  19. 19.
    Buckstein R, Pennell N, Berinstein NL. What is remission in follicular lymphoma and what is its relevance? Best Pract Res Clin Haematol. 2005;18:27–56.CrossRefPubMedGoogle Scholar
  20. 20.
    Bachy E, Brice P, Delarue R, Brousse N, Haioun C, Le Gouill S, et al. Long-term follow-up of patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on survival—a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2010;28:822–9.Google Scholar
  21. 21.
    Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007;25:1986–92.CrossRefPubMedGoogle Scholar
  23. 23.
    Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004;22:4711–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.CrossRefPubMedGoogle Scholar
  25. 25.
    Janikova A, Bolcak K, Pavlik T, Mayer J, Kral Z. Value of [18F]fluorodeoxyglucose positron emission tomography in the management of follicular lymphoma: the end of a dilemma? Clin Lymphoma Myeloma. 2008;8:287–93.CrossRefPubMedGoogle Scholar
  26. 26.
    van Oers MH, Tonnissen E, Van Glabbeke M, Giurgea L, Jansen JH, Klasa R, et al. BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study. J Clin Oncol. 2010;28:2246–52.Google Scholar
  27. 27.
    Biagi JJ, Seymour JF. Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood. 2002;99:4265–75.CrossRefPubMedGoogle Scholar
  28. 28.
    Katzenberger T, Kalla J, Leich E, Stocklein H, Hartmann E, Barnickel S, et al. A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36. Blood. 2009;113:1053–61.CrossRefPubMedGoogle Scholar
  29. 29.
    Rambaldi A, Carlotti E, Oldani E, Della Starza I, Baccarani M, Cortelazzo S, et al. Quantitative PCR of bone marrow BCL2/IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma. Blood. 2005;105:3428–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, et al. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood. 1994;84:1043–9.PubMedGoogle Scholar
  31. 31.
    Hoglund M, Sehn L, Connors JM, Gascoyne RD, Siebert R, Sall T, et al. Identification of cytogenetic subgroups and karyotypic pathways of clonal evolution in follicular lymphomas. Genes Chromosomes Cancer. 2004;39:195–204.CrossRefPubMedGoogle Scholar
  32. 32.
    Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159–69.CrossRefPubMedGoogle Scholar
  33. 33.
    Byers RJ, Sakhinia E, Joseph P, Glennie C, Hoyland JA, Menasce LP, et al. Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling. Blood. 2008;111:4764–70.CrossRefPubMedGoogle Scholar
  34. 34.
    Glas AM, Knoops L, Delahaye L, Kersten MJ, Kibbelaar RE, Wessels LA, et al. Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma. J Clin Oncol. 2007;25:390–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Wahlin BE, Sander B, Christensson B, Kimby E. CD8+ T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res. 2007;13:388–97.CrossRefPubMedGoogle Scholar
  36. 36.
    Canioni D, Salles G, Mounier N, Brousse N, Keuppens M, Morchhauser F, et al. High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol. 2008;26:440–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Farinha P, Masoudi H, Skinnider BF, Shumansky K, Spinelli JJ, Gill K, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood. 2005;106:2169–74.CrossRefPubMedGoogle Scholar
  38. 38.
    Lee AM, Clear AJ, Calaminici M, Davies AJ, Jordan S, MacDougall F, et al. Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol. 2006;24:5052–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Taskinen M, Karjalainen-Lindsberg ML, Nyman H, Eerola LM, Leppa S. A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone. Clin Cancer Res. 2007;13:5784–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Jacob MC, Piccinni MP, Bonnefoix T, Sotto MF, Couderc P, Bensa JC, et al. T lymphocytes from invaded lymph nodes in patients with B-cell-derived non-Hodgkin’s lymphoma: reactivity toward the malignant clone. Blood. 1990;75:1154–62.PubMedGoogle Scholar
  41. 41.
    Dallman C, Johnson PW, Packham G. Differential regulation of cell survival by CD40. Apoptosis. 2003;8:45–53.CrossRefPubMedGoogle Scholar
  42. 42.
    Carbone A, Gloghini A, Cabras A, Elia G. The Germinal centre-derived lymphomas seen through their cellular microenvironment. Br J Haematol. 2009;145:468–80.CrossRefPubMedGoogle Scholar
  43. 43.
    Wahlin BE, Aggarwal M, Montes-Moreno S, Gonzalez LF, Roncador G, Sanchez-Verde L, et al. A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1—positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin Cancer Res. 2009;16:637–50.CrossRefGoogle Scholar
  44. 44.
    Ai WZ, Hou JZ, Zeiser R, Czerwinski D, Negrin RS, Levy R. Follicular lymphoma B cells induce the conversion of conventional CD4+ T cells to T-regulatory cells. Int J Cancer. 2009;124:239–44.CrossRefPubMedGoogle Scholar
  45. 45.
    Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin’s lymphoma. Cancer Res. 2009;69:5522–30.CrossRefPubMedGoogle Scholar
  46. 46.
    Fehervari Z, Sakaguchi S. CD4+ T-regs and immune control. J Clin Invest. 2004;114:1209–17.PubMedGoogle Scholar
  47. 47.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61.PubMedGoogle Scholar
  48. 48.
    Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 2006;108:2957–64.CrossRefPubMedGoogle Scholar
  49. 49.
    Farinha P, Al-Tourah A, Gill K, Klasa R, Connors JM, Gascoyne RD. The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood. 2010;115:289–95.CrossRefPubMedGoogle Scholar
  50. 50.
    Sweetenham JW, Goldman B, Leblanc ML, Cook JR, Tubbs RR, Press OW, et al. Prognostic value of regulatory T cells, lymphoma-associated macrophages, and MUM-1 expression in follicular lymphoma treated before and after the introduction of monoclonal antibody therapy: a Southwest Oncology Group Study. Ann Oncol. 2010;21(6):1196–202.Google Scholar
  51. 51.
    Lim HW, Hillsamer P, Kim CH. Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J Clin Invest. 2004;114:1640–9.PubMedGoogle Scholar
  52. 52.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMedGoogle Scholar
  53. 53.
    Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol. 2007;19:309–14.CrossRefPubMedGoogle Scholar
  54. 54.
    Carreras J, Lopez-Guillermo A, Roncador G, Villamor N, Colomo L, Martinez A, et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol. 2009;27:1470–6.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  1. 1.Centre J. BernardService d’HématologieLe MansFrance
  2. 2.Service d’HématologieCHU PontchaillouRennesFrance
  3. 3.Service d’HématologieUMR, CNRS 5235, CHU Saint-EloiMontpellierFrance

Personalised recommendations