Keywords
diffuse large B-cell lymphoma, central nervous system, intrathecal therapy
How to Cite
Lavalle, J., & Colucci, M. (2019). Risk factors and prophylaxis of the central nervous system in diffuse large B-cell lymphoma. Journal of Hematology, 21(2), 177–187. Retrieved from https://revistahematologia.com.ar/index.php/Revista/article/view/151
Abstract
Central nervous system (CNS) onset involvement in diffuse large B-cell lymphoma (DLBCL) is a rare event. It is a little more frequent the isolated relapse in CNS, after the treatment -5% of the cases-, being a very serious complication. For this reason, it has been tried for a long time to detect subgroups of patients with a greater probability of recurrence in the CNS. These subgroups are identified based on the presence of risk factors associated with subsequent CNS relapse. The most effective prophylactic regimen has not been determined with certainty. The use of intrathecal chemotherapy appears not to be sufficient to reduce CNS relapse, since drugs injected locally into the cerebrospinal fluid do not penetrate into the CNS parenchyma. Therefore, it is preferred -in patients with a high risk of relapse in CNS- the use of systemic agents in high doses, that reach cytotoxic levels in the cerebral parenchyma.
References
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2. Ferreri AJM, Assanelli A, Crocchiolo R et al.Central nervous system dissemination in immu-nocompetent patients with aggressive lympho-mas: incidence, risk factors and therapeutic op-tions. Hematol Onco. 27: 61–70. 2009.
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6. Fletcher CD, Kahl BS. Central nervous system involvement in diffuse large B-cell lymphoma: an analysis of risk and prevention strategies in the post-rituximab era. Leuk Lymphoma. 55 (10): 2228-2240. Feb 2014.
7. Alvarez R, Dupuis J, Plonquet A et al. Clinical relevance of flow cytometric immunophenoty-ping of the cerebrospinal fluid in patients with diffuse large B-cell lymphoma. Ann Oncol. 23: 1274-1279. Sep 2011.
8. Feugier P, Virion JM, Tilly H et al. Incidence and risk factors for central nervous system occurren-ce in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol. 15: 129-133. 2004.
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11. Boehme V, Zeynalova S, Kloess M et al. Inci-dence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol. 18: 149-117. Oct 2006.
12. Hegde U, Filie A, Little RF et al. High inciden-ce 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. 2005.
13. Boehme V, Schmitz N, Zeynalova S et al. CNS events in elderly patients with aggressive lym-phoma 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 Lym-phoma Study Group (DSHNHL). Blood. 113 (17): 3896-3902. Ap 2009.
14. Kumar A, MD1; Vanderplas A, LaCasce AS et al. Lack of Benefit of Central Nervous System Prophylaxis for Diffuse Large B-Cell Lympho-ma in the Rituximab Era. Cancer. 118: 2944-51. Jun 2012.
15. Guirguis HR, Cheung MC, Mahrous M et al. Impact of central nervous system (CNS) pro-phylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature. BJH. 159: 39-49. Jul 2012.
16. Ferreri AJM, Assanelli A, Crocchiolo R et al. Central nervous system dissemination in immu-nocompetent patients with aggressive lympho-mas: incidence, risk factors and therapeutic op-tions. Hematol Oncol. 27: 61–70. Feb 2009.
17. Benevolo G, Chiappella A, Vitolo U. The risk of CNS involvement in aggressive lymphomas in the rituximab era. Expert Rev. Hematol. 6 (6): 643–652. 2013.
18. Siegal T, Goldschmidt N. CNS prophylaxis in di-ffuse large B-cell lymphoma: If, when, how and for whom? Blood Reviews. 26: 97–106. 2012.
19. Kridel R, Dietrich PY. Prevention of CNS relap-se in diffuse large B-cell lymphoma. Lancet On-col. 12: 1258–66. Sep 2011.
20. van Besien K, Ha CS, Murphy S et al. Risk Fac-tors, Treatment, and Outcome of Central Ner-vous System Recurrence in Adults With Inter-mediate-Grade and Immunoblastic Lymphoma. Blood. 91 (4): 1178-1184. Feb 1998.
21. Ferreri AJM. Risk of CNS dissemination in ex-tranodal lymphomas. Lancet Oncol. 15: 159–69. Ap 2014.
22. McMillan A, Ardeshna KM, Cwynarski K et al. Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology. British Journal of Haematology. 163: 168–181. Ag 2013.
23. Castellino A, Vitolo U. The management and treatment of primary testicular lymphoma. He-matology Education: the education program for the annual congress of the European Hematology Association. 8 (1): 123-132. Jun 2014.
24. Lenz G, Staudt LM. Aggressive Lymphomas. N Engl J Med. 362 (15):1417-29. Ap 2010.
25. Rosenwald A, Wright G, Chan WC et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lympho-ma. N Engl J Med. 346 (25): 1937-1947. Jun 2002.
26. Savage K, Johnson N, Ben-Neriah S et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 114(17): 3533–3537. 2009.
27. Aukema SM, Siebert R, Schuuring E et al. Dou-ble-hit B-cell lymphomas. Blood. 117(8): 2319-2331. 2011.
28. Kridel R, Dietrich PY. Prevention of CNS relap-se in diffuse large B-cell lymphoma. Lancet On-col. 12: 1258–66. Dic 2012.
29. Wilson WH, Bromberg JEC, Stetler-Stevenson M et al. Detection and outcome of occult lepto-meningeal disease in diffuse large B-cell lym-phoma and Burkitt lymphoma. Haematologica. 99 (7): 1228-1235. Mar 2014.30. Benevolo G, Stacchini A, Spina M et al. Final re-sults of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination. Blood. 120(16): 3222-3228. Oct 2012.
31. Tomita N, Kodama F, Kanamori H et al. Pro-phylactic Intrathecal Methotrexate and Hy-drocortisone Reduces Central Nervous Sys-tem Recurrence and Improves Survival in Aggressive Non-Hodgkin Lymphoma. Cancer. 2002;95:576–80.
32. Bernstein SH, Unger JM, LeBlanc M et al. Na-tural 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 (1): 114-119. Jan 2009.
33. Benevolo G, Chiappella A, Vitolo U. CNS pro-phylaxis in aggressive lymphomas: for whom and how. Hematol Oncol. 31 (1): 89-91. 2013.
34. Arkenau HT, Chong G, Cunningham D et al. The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma. An-nals of Oncolog. 18: 541–545. 2007.
35. Vitolo U, Chiappella A, Ferreri AJM et al. First-Line Treatment for Primary Testicular Diffuse Large B-Cell Lymphoma With Rituxi-mab-CHOP, CNS Prophylaxis, and Contralateral Testis Irradiation: Final Results of an Internatio-nal Phase II Trial. J Clin Oncol. 29: 2766-2772. 2011.
36. Haioun C, Besson C, Lepage E et al. Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lym-phoma uniformly treated and receiving intrathe-cal central nervous system prophylaxis: A GELA study on 974 patients. Annals of Oncology. 11: 685-690. 2000.
37. Cheung CW, Burton C, Smith P et al. Central nervous system chemoprophylaxis in non-Hodg-kin lymphoma: current practice in the UK. BJH. 131: 193-200. Jul 2005.
38. Joerger M, Ferreri AJM, Krahenbuhl S et al. Do-sing algorithm to target a predefined AUC in pa-tients with primary central nervous system lym-phoma receiving high dose methotrexate. BJCP. 73 (2): 240-247. Aug 2011.
39. Ferreri AJM, Reni M. Prognostic Factors in Primary Central Nervous System Lymphomas. Hematol Oncol Clin of N Am. 19 (4): 629-649. 2005.
40. Schmiegelow K. Advances in individual pre-diction of methotrexate toxicity: a review. BJM. 46(5): 489-503. Sep 2009.
41. McMillan A. Central nervous system-directed preventive therapy in adults with lymphoma. BJH. 131: 13-21. 2005.
2. Ferreri AJM, Assanelli A, Crocchiolo R et al.Central nervous system dissemination in immu-nocompetent patients with aggressive lympho-mas: incidence, risk factors and therapeutic op-tions. Hematol Onco. 27: 61–70. 2009.
3. Abramson JS, Hellmann M, Barnes JA et al. Intravenous Methotrexate as Central Nervous System (CNS) Prophylaxis Is Associated With a Low Risk of CNS Recurrence in High-Risk Patients With Diffuse Large B-Cell Lymphoma. Cancer. 116: 4283-90. Sep 2010.
4. Kim SJ, Yong Oh S, Kim JS et al. Secondary central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma: a therapeutic dilema. Ann Hematol. 90: 539-546.vado, participación de testículo, mama, senos para-nasales, sitios parameníngeos, médula ósea, riñón y/o glándulas suprarrenales.Los estudios realizados en la era pre-R han mos-trado evidencia contradictoria sobre el papel de la profilaxis intratecal en pacientes de alto riesgo con LDCGB, excepto en los pacientes con afectación testicular. Grandes estudios no mostraron ningún beneficio añadido de la profilaxis intratecal. En la era del R, los estudios han mostrado una disminu-ción de la recaída del SNC, probablemente debido a un mejor control de la enfermedad sistémica con esta droga, ya que no atraviesa la barrera hematoen-cefálica.El beneficio de la quimioprofilaxis del SNC en la era R continúa siendo incierto por falta de pruebas. Los pacientes pueden ser tratados con quimiopro-filaxis sistémica con o sin profilaxis intratecal de forma individual. La experiencia del médico y de la institución debe tenerse en cuenta al considerar la profilaxis sistémica, ya que requiere una estrecha vigilancia de los niveles de MTX, de las toxicidades asociadas y el rescate oportuno con leucovorina.
5. Ghose A, Kundu R, Latif T. Prophylactic CNS di-rected therapy in system diffuse large B cell lym-phoma. Oncol/Hematol. 91: 292-303. Feb 2014.
6. Fletcher CD, Kahl BS. Central nervous system involvement in diffuse large B-cell lymphoma: an analysis of risk and prevention strategies in the post-rituximab era. Leuk Lymphoma. 55 (10): 2228-2240. Feb 2014.
7. Alvarez R, Dupuis J, Plonquet A et al. Clinical relevance of flow cytometric immunophenoty-ping of the cerebrospinal fluid in patients with diffuse large B-cell lymphoma. Ann Oncol. 23: 1274-1279. Sep 2011.
8. Feugier P, Virion JM, Tilly H et al. Incidence and risk factors for central nervous system occurren-ce in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol. 15: 129-133. 2004.
9. Hollender A, Kvaloy S, Nome O et al. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 13: 1099-1107. 2002.
10. Villa D, Connors JM, Shenkie TN et al. Inciden-ce and risk factors for central nervous system relapse in patients with diffuse large B-cell lym-phoma: the impact of the addition of rituximab to CHOP chemotherapy. Ann Oncol. 21: 1046-1052. Oct 2009.
11. Boehme V, Zeynalova S, Kloess M et al. Inci-dence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol. 18: 149-117. Oct 2006.
12. Hegde U, Filie A, Little RF et al. High inciden-ce 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. 2005.
13. Boehme V, Schmitz N, Zeynalova S et al. CNS events in elderly patients with aggressive lym-phoma 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 Lym-phoma Study Group (DSHNHL). Blood. 113 (17): 3896-3902. Ap 2009.
14. Kumar A, MD1; Vanderplas A, LaCasce AS et al. Lack of Benefit of Central Nervous System Prophylaxis for Diffuse Large B-Cell Lympho-ma in the Rituximab Era. Cancer. 118: 2944-51. Jun 2012.
15. Guirguis HR, Cheung MC, Mahrous M et al. Impact of central nervous system (CNS) pro-phylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature. BJH. 159: 39-49. Jul 2012.
16. Ferreri AJM, Assanelli A, Crocchiolo R et al. Central nervous system dissemination in immu-nocompetent patients with aggressive lympho-mas: incidence, risk factors and therapeutic op-tions. Hematol Oncol. 27: 61–70. Feb 2009.
17. Benevolo G, Chiappella A, Vitolo U. The risk of CNS involvement in aggressive lymphomas in the rituximab era. Expert Rev. Hematol. 6 (6): 643–652. 2013.
18. Siegal T, Goldschmidt N. CNS prophylaxis in di-ffuse large B-cell lymphoma: If, when, how and for whom? Blood Reviews. 26: 97–106. 2012.
19. Kridel R, Dietrich PY. Prevention of CNS relap-se in diffuse large B-cell lymphoma. Lancet On-col. 12: 1258–66. Sep 2011.
20. van Besien K, Ha CS, Murphy S et al. Risk Fac-tors, Treatment, and Outcome of Central Ner-vous System Recurrence in Adults With Inter-mediate-Grade and Immunoblastic Lymphoma. Blood. 91 (4): 1178-1184. Feb 1998.
21. Ferreri AJM. Risk of CNS dissemination in ex-tranodal lymphomas. Lancet Oncol. 15: 159–69. Ap 2014.
22. McMillan A, Ardeshna KM, Cwynarski K et al. Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology. British Journal of Haematology. 163: 168–181. Ag 2013.
23. Castellino A, Vitolo U. The management and treatment of primary testicular lymphoma. He-matology Education: the education program for the annual congress of the European Hematology Association. 8 (1): 123-132. Jun 2014.
24. Lenz G, Staudt LM. Aggressive Lymphomas. N Engl J Med. 362 (15):1417-29. Ap 2010.
25. Rosenwald A, Wright G, Chan WC et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lympho-ma. N Engl J Med. 346 (25): 1937-1947. Jun 2002.
26. Savage K, Johnson N, Ben-Neriah S et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 114(17): 3533–3537. 2009.
27. Aukema SM, Siebert R, Schuuring E et al. Dou-ble-hit B-cell lymphomas. Blood. 117(8): 2319-2331. 2011.
28. Kridel R, Dietrich PY. Prevention of CNS relap-se in diffuse large B-cell lymphoma. Lancet On-col. 12: 1258–66. Dic 2012.
29. Wilson WH, Bromberg JEC, Stetler-Stevenson M et al. Detection and outcome of occult lepto-meningeal disease in diffuse large B-cell lym-phoma and Burkitt lymphoma. Haematologica. 99 (7): 1228-1235. Mar 2014.30. Benevolo G, Stacchini A, Spina M et al. Final re-sults of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination. Blood. 120(16): 3222-3228. Oct 2012.
31. Tomita N, Kodama F, Kanamori H et al. Pro-phylactic Intrathecal Methotrexate and Hy-drocortisone Reduces Central Nervous Sys-tem Recurrence and Improves Survival in Aggressive Non-Hodgkin Lymphoma. Cancer. 2002;95:576–80.
32. Bernstein SH, Unger JM, LeBlanc M et al. Na-tural 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 (1): 114-119. Jan 2009.
33. Benevolo G, Chiappella A, Vitolo U. CNS pro-phylaxis in aggressive lymphomas: for whom and how. Hematol Oncol. 31 (1): 89-91. 2013.
34. Arkenau HT, Chong G, Cunningham D et al. The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma. An-nals of Oncolog. 18: 541–545. 2007.
35. Vitolo U, Chiappella A, Ferreri AJM et al. First-Line Treatment for Primary Testicular Diffuse Large B-Cell Lymphoma With Rituxi-mab-CHOP, CNS Prophylaxis, and Contralateral Testis Irradiation: Final Results of an Internatio-nal Phase II Trial. J Clin Oncol. 29: 2766-2772. 2011.
36. Haioun C, Besson C, Lepage E et al. Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lym-phoma uniformly treated and receiving intrathe-cal central nervous system prophylaxis: A GELA study on 974 patients. Annals of Oncology. 11: 685-690. 2000.
37. Cheung CW, Burton C, Smith P et al. Central nervous system chemoprophylaxis in non-Hodg-kin lymphoma: current practice in the UK. BJH. 131: 193-200. Jul 2005.
38. Joerger M, Ferreri AJM, Krahenbuhl S et al. Do-sing algorithm to target a predefined AUC in pa-tients with primary central nervous system lym-phoma receiving high dose methotrexate. BJCP. 73 (2): 240-247. Aug 2011.
39. Ferreri AJM, Reni M. Prognostic Factors in Primary Central Nervous System Lymphomas. Hematol Oncol Clin of N Am. 19 (4): 629-649. 2005.
40. Schmiegelow K. Advances in individual pre-diction of methotrexate toxicity: a review. BJM. 46(5): 489-503. Sep 2009.
41. McMillan A. Central nervous system-directed preventive therapy in adults with lymphoma. BJH. 131: 13-21. 2005.
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