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Secondary central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma: a therapeutic dilemma

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Secondary central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) includes an isolated CNS relapse or CNS involvement with systemic disease progression. This rare but fatal clinical problem still remains a therapeutic dilemma in the management of DLBCL. However, there are limited data about its treatment outcome. In this study, we gathered 73 cases with secondary CNS involvement of DLBCL from 11 hospitals in Korea. The data were retrospectively compared according to the status of systemic disease (isolated vs. combined CNS involvement) and the use of high-dose methotrexate treatment (HD MTX). Twenty-nine patients showed isolated CNS involvement while 44 had combined CNS involvement with systemic relapse or progression. Thirty-three cases (45.2%) occurred within 6 months from the initial diagnosis, and the majority of these were associated with systemic disease relapse or progression (n = 27). In isolated CNS involvement, HD MTX resulted in fewer treatment failures (3/11) than the other treatments such as other salvage chemotherapy and/or radiotherapy/intraventricular chemotherapy (14/15). However, neither HD MTX nor other treatments were effective at reducing the treatment failure rate in combined CNS involvement (8/10 and 23/30, respectively). Thus, isolated CNS involvement had a better survival than combined involvement (P = 0.008), but systemic disease progression was the main cause of death in combined as well as isolated CNS involvement. In conclusion, the prognosis of secondary CNS involvement was dismal even after intensive chemotherapy using HD MTX. Further research focusing on the development of an optimal treatment strategy is warranted.

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  1. Haioun C, Besson C, Lepage E, Thieblemont C, Simon D, Rose C, Tilly H, Sonet A, Lederlin P, Attal M, Briere J, Reyes F (2000) Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 11:685–690

    Article  PubMed  CAS  Google Scholar 

  2. Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H (2002) Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol 13:1099–1107

    Article  PubMed  CAS  Google Scholar 

  3. Hegde U, Filie A, Little RF, Janik JE, Grant N, Steinberg SM, Dunleavy K, Jaffe ES, Abati A, Stetler-Stevenson M, Wilson WH (2005) High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood 105:496–502

    Article  PubMed  CAS  Google Scholar 

  4. van Besien K, Ha CS, Murphy S, McLaughlin P, Rodriguez A, Amin K, Forman A, Romaguera J, Hagemeister F, Younes A, Bachier C, Sarris A, Sobocinski KS, Cox JD, Cabanillas F (1998) Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91:1178–1184

    PubMed  Google Scholar 

  5. MacKintosh FR, Colby TV, Podolsky WJ, Burke JS, Hoppe RT, Rosenfelt FP, Rosenberg SA, Kaplan HS (1982) Central nervous system involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer 49:586–595

    Article  PubMed  CAS  Google Scholar 

  6. Bierman P, Giglio P (2005) Diagnosis and treatment of central nervous system involvement in non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am 19:597–609, v

    Article  PubMed  Google Scholar 

  7. Tomita N, Kodama F, Kanamori H, Motomura S, Ishigatsubo Y (2006) Secondary central nervous system lymphoma. Int J Hematol 84:128–135

    Article  PubMed  Google Scholar 

  8. Dietrich PY, Dietrich PY (2009) Intrathecal MTX for DLBCL: from an inappropriate prophylactic tradition to a medical error? Blood 114:1999, author reply 1999

    Article  PubMed  CAS  Google Scholar 

  9. Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M (2009) Response: intrathecal methotrexate and central nervous system events. Blood 114:1999–2000

    Article  PubMed  CAS  Google Scholar 

  10. Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M (2009) CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood 113:3896–3902

    Article  PubMed  CAS  Google Scholar 

  11. Doolittle ND, Abrey LE, Shenkier TN, Tali S, Bromberg JE, Neuwelt EA, Soussain C, Jahnke K, Johnston P, Illerhaus G, Schiff D, Batchelor T, Montoto S, Kraemer DF, Zucca E (2008) Brain parenchyma involvement as isolated central nervous system relapse of systemic non-Hodgkin lymphoma: an International Primary CNS Lymphoma Collaborative Group report. Blood 111:1085–1093

    Article  PubMed  CAS  Google Scholar 

  12. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244

    PubMed  CAS  Google Scholar 

  13. Schemper M, Smith TL (1996) A note on quantifying follow-up in studies of failure time. Control Clin Trials 17:343–346

    Article  PubMed  CAS  Google Scholar 

  14. van Besien K, Gisselbrecht C, Pfreundschuh M, Zucca E (2008) Secondary lymphomas of the central nervous system: risk, prophylaxis and treatment. Leuk Lymphoma 49(Suppl 1):52–58

    Article  PubMed  Google Scholar 

  15. Bernstein SH, Unger JM, Leblanc M, Friedberg J, Miller TP, Fisher RI (2009) Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG 8516—the Southwest Oncology Group. J Clin Oncol 27:114–119

    Article  PubMed  Google Scholar 

  16. Tilly H, Lepage E, Coiffier B, Blanc M, Herbrecht R, Bosly A, Attal M, Fillet G, Guettier C, Molina TJ, Gisselbrecht C, Reyes F (2003) Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102:4284–4289

    Article  PubMed  CAS  Google Scholar 

  17. Villa D, Connors JM, Shenkier TN, Gascoyne RD, Sehn LH, Savage KJ (2009) Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. Ann Oncol 21:1046–1052

    Article  PubMed  Google Scholar 

  18. Shimazu Y, Notohara K, Ueda Y (2009) Diffuse large B-cell lymphoma with central nervous system relapse: prognosis and risk factors according to retrospective analysis from a single-center experience. Int J Hematol 89:577–583

    Article  PubMed  CAS  Google Scholar 

  19. Feugier P, Virion JM, Tilly H, Haioun C, Marit G, Macro M, Bordessoule D, Recher C, Blanc M, Molina T, Lederlin P, Coiffier B (2004) Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol 15:129–133

    Article  PubMed  CAS  Google Scholar 

  20. Uhm JE, Kim KH, Yi SY, Chang MH, Park KW, Kong DS, Lee JI, do Nam H, Park W, do Lim H, Kim SJ, Kim K, Ko YH, Kim WS (2009) A retrospective study to compare two methotrexate-based regimens for primary central nervous system lymphoma. Leuk Lymphoma 50:1110–1118

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Won Seog Kim or Cheolwon Suh.

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Kim, S.J., Oh, S.Y., Kim, J.S. et al. Secondary central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma: a therapeutic dilemma. Ann Hematol 90, 539–546 (2011).

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