Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab
Identifieur interne : 001F84 ( Istex/Corpus ); précédent : 001F83; suivant : 001F85Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab
Auteurs : P. Feugier ; J. M. Virion ; H. Tilly ; C. Haioun ; G. Marit ; M. Macro ; D. Bordessoule ; C. Recher ; M. Blanc ; T. Molina ; P. Lederlin ; B. CoiffierSource :
- Annals of Oncology [ 0923-7534 ] ; 2004-01.
English descriptors
- KwdEn :
- Teeft :
- Actuarial risk, Acvbp, Acvbp regimen, Aggressive lymphoma, Complete remission, Diffuse lymphoma, Direct intrathecal administration, Elderly patients, Extranodal sites, Gela study, International prognostic index, Intrathecal, Intrathecal injections, Lactate dehydrogenase, Leuk lymphoma, Localization, Lymphoma, Methotrexate, Multivariate analysis, Nervous system, Overall survival, Partial remission, Performance status, Poor performance status, Poor prognosis, Prophylaxis, Regimen, Regression analysis, Relapse, Risk factors, Rituximab, Rituximab decreases, Rituximab diffusion, Rituximab group, System involvement, System occurrence, System relapse, Systemic chemotherapy, Systemic recurrence, Systemic relapse, Treatment group, Treatment protocol, Variable number.
Abstract
Background: The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma. Patients and methods: We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol. Results: We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months. Conclusions: Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.
Url:
DOI: 10.1093/annonc/mdh013
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ISTEX:898B857B28F5AAACD7600687FEB4258B1CCFFFBDLe document en format XML
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Tilly</name><affiliation><mods:affiliation>Centre Henri Becquerel, Rouen;</mods:affiliation></affiliation></author><author><name sortKey="Haioun, C" sort="Haioun, C" uniqKey="Haioun C" first="C." last="Haioun">C. Haioun</name><affiliation><mods:affiliation>Service Hématologie, Hôpital Henri Mondor, AP-HP, Créteil;</mods:affiliation></affiliation></author><author><name sortKey="Marit, G" sort="Marit, G" uniqKey="Marit G" first="G." last="Marit">G. Marit</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Bordeaux;</mods:affiliation></affiliation></author><author><name sortKey="Macro, M" sort="Macro, M" uniqKey="Macro M" first="M." last="Macro">M. Macro</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Caen;</mods:affiliation></affiliation></author><author><name sortKey="Bordessoule, D" sort="Bordessoule, D" uniqKey="Bordessoule D" first="D." last="Bordessoule">D. Bordessoule</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Limoges;</mods:affiliation></affiliation></author><author><name sortKey="Recher, C" sort="Recher, C" uniqKey="Recher C" first="C." last="Recher">C. Recher</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Toulouse;</mods:affiliation></affiliation></author><author><name sortKey="Blanc, M" sort="Blanc, M" uniqKey="Blanc M" first="M." last="Blanc">M. Blanc</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier, Chambéry;</mods:affiliation></affiliation></author><author><name sortKey="Molina, T" sort="Molina, T" uniqKey="Molina T" first="T." last="Molina">T. Molina</name><affiliation><mods:affiliation>Service Anatomo-Pathologie, Hôtel Dieu, AP-HP, Paris;</mods:affiliation></affiliation></author><author><name sortKey="Lederlin, P" sort="Lederlin, P" uniqKey="Lederlin P" first="P." last="Lederlin">P. 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Coiffier</name><affiliation><mods:affiliation>Service Hématologie, Hospices Civils, Lyon, France</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:898B857B28F5AAACD7600687FEB4258B1CCFFFBD</idno><date when="2004" year="2004">2004</date><idno type="doi">10.1093/annonc/mdh013</idno><idno type="url">https://api.istex.fr/ark:/67375/HXZ-993BMG1R-B/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001F84</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001F84</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</title><author><name sortKey="Feugier, P" sort="Feugier, P" uniqKey="Feugier P" first="P." last="Feugier">P. Feugier</name><affiliation><mods:affiliation>Service Hématologie,</mods:affiliation></affiliation></author><author><name sortKey="Virion, J M" sort="Virion, J M" uniqKey="Virion J" first="J. M." last="Virion">J. M. Virion</name><affiliation><mods:affiliation>Service Informatique Médicale, Hôpitaux de Brabois, Nancy;</mods:affiliation></affiliation></author><author><name sortKey="Tilly, H" sort="Tilly, H" uniqKey="Tilly H" first="H." last="Tilly">H. Tilly</name><affiliation><mods:affiliation>Centre Henri Becquerel, Rouen;</mods:affiliation></affiliation></author><author><name sortKey="Haioun, C" sort="Haioun, C" uniqKey="Haioun C" first="C." last="Haioun">C. Haioun</name><affiliation><mods:affiliation>Service Hématologie, Hôpital Henri Mondor, AP-HP, Créteil;</mods:affiliation></affiliation></author><author><name sortKey="Marit, G" sort="Marit, G" uniqKey="Marit G" first="G." last="Marit">G. Marit</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Bordeaux;</mods:affiliation></affiliation></author><author><name sortKey="Macro, M" sort="Macro, M" uniqKey="Macro M" first="M." last="Macro">M. Macro</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Caen;</mods:affiliation></affiliation></author><author><name sortKey="Bordessoule, D" sort="Bordessoule, D" uniqKey="Bordessoule D" first="D." last="Bordessoule">D. Bordessoule</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Limoges;</mods:affiliation></affiliation></author><author><name sortKey="Recher, C" sort="Recher, C" uniqKey="Recher C" first="C." last="Recher">C. Recher</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier Universitaire, Toulouse;</mods:affiliation></affiliation></author><author><name sortKey="Blanc, M" sort="Blanc, M" uniqKey="Blanc M" first="M." last="Blanc">M. Blanc</name><affiliation><mods:affiliation>Service Hématologie, Centre Hospitalier, Chambéry;</mods:affiliation></affiliation></author><author><name sortKey="Molina, T" sort="Molina, T" uniqKey="Molina T" first="T." last="Molina">T. Molina</name><affiliation><mods:affiliation>Service Anatomo-Pathologie, Hôtel Dieu, AP-HP, Paris;</mods:affiliation></affiliation></author><author><name sortKey="Lederlin, P" sort="Lederlin, P" uniqKey="Lederlin P" first="P." last="Lederlin">P. Lederlin</name><affiliation><mods:affiliation>Service Hématologie,</mods:affiliation></affiliation></author><author><name sortKey="Coiffier, B" sort="Coiffier, B" uniqKey="Coiffier B" first="B." last="Coiffier">B. Coiffier</name><affiliation><mods:affiliation>Service Hématologie, Hospices Civils, Lyon, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Oncology</title><title level="j" type="abbrev">Ann Oncol</title><idno type="ISSN">0923-7534</idno><idno type="eISSN">1569-8041</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2004-01">2004-01</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="129">129</biblScope><biblScope unit="page" to="133">133</biblScope></imprint><idno type="ISSN">0923-7534</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0923-7534</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>aggressive non-Hodgkin’s lymphoma, central nervous system occurrence, risk factors, rituximab</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Actuarial risk</term><term>Acvbp</term><term>Acvbp regimen</term><term>Aggressive lymphoma</term><term>Complete remission</term><term>Diffuse lymphoma</term><term>Direct intrathecal administration</term><term>Elderly patients</term><term>Extranodal sites</term><term>Gela study</term><term>International prognostic index</term><term>Intrathecal</term><term>Intrathecal injections</term><term>Lactate dehydrogenase</term><term>Leuk lymphoma</term><term>Localization</term><term>Lymphoma</term><term>Methotrexate</term><term>Multivariate analysis</term><term>Nervous system</term><term>Overall survival</term><term>Partial remission</term><term>Performance status</term><term>Poor performance status</term><term>Poor prognosis</term><term>Prophylaxis</term><term>Regimen</term><term>Regression analysis</term><term>Relapse</term><term>Risk factors</term><term>Rituximab</term><term>Rituximab decreases</term><term>Rituximab diffusion</term><term>Rituximab group</term><term>System involvement</term><term>System occurrence</term><term>System relapse</term><term>Systemic chemotherapy</term><term>Systemic recurrence</term><term>Systemic relapse</term><term>Treatment group</term><term>Treatment protocol</term><term>Variable number</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma. Patients and methods: We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol. Results: We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months. Conclusions: Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.</div></front></TEI><istex><corpusName>oup</corpusName><keywords><teeft><json:string>rituximab</json:string><json:string>relapse</json:string><json:string>lymphoma</json:string><json:string>intrathecal</json:string><json:string>prophylaxis</json:string><json:string>acvbp</json:string><json:string>elderly patients</json:string><json:string>methotrexate</json:string><json:string>diffuse lymphoma</json:string><json:string>risk factors</json:string><json:string>rituximab group</json:string><json:string>aggressive lymphoma</json:string><json:string>regimen</json:string><json:string>international prognostic index</json:string><json:string>extranodal sites</json:string><json:string>localization</json:string><json:string>system involvement</json:string><json:string>performance status</json:string><json:string>poor prognosis</json:string><json:string>multivariate analysis</json:string><json:string>systemic relapse</json:string><json:string>treatment group</json:string><json:string>poor performance status</json:string><json:string>intrathecal injections</json:string><json:string>acvbp regimen</json:string><json:string>actuarial risk</json:string><json:string>regression analysis</json:string><json:string>complete remission</json:string><json:string>partial remission</json:string><json:string>rituximab diffusion</json:string><json:string>system occurrence</json:string><json:string>rituximab decreases</json:string><json:string>variable number</json:string><json:string>treatment protocol</json:string><json:string>overall survival</json:string><json:string>systemic chemotherapy</json:string><json:string>systemic recurrence</json:string><json:string>nervous system</json:string><json:string>direct intrathecal administration</json:string><json:string>gela study</json:string><json:string>lactate dehydrogenase</json:string><json:string>leuk lymphoma</json:string><json:string>system relapse</json:string></teeft></keywords><author><json:item><name>P. Feugier</name><affiliations><json:string>Service Hématologie,</json:string></affiliations></json:item><json:item><name>J. M. Virion</name><affiliations><json:string>Service Informatique Médicale, Hôpitaux de Brabois, Nancy;</json:string></affiliations></json:item><json:item><name>H. Tilly</name><affiliations><json:string>Centre Henri Becquerel, Rouen;</json:string></affiliations></json:item><json:item><name>C. Haioun</name><affiliations><json:string>Service Hématologie, Hôpital Henri Mondor, AP-HP, Créteil;</json:string></affiliations></json:item><json:item><name>G. Marit</name><affiliations><json:string>Service Hématologie, Centre Hospitalier Universitaire, Bordeaux;</json:string></affiliations></json:item><json:item><name>M. Macro</name><affiliations><json:string>Service Hématologie, Centre Hospitalier Universitaire, Caen;</json:string></affiliations></json:item><json:item><name>D. Bordessoule</name><affiliations><json:string>Service Hématologie, Centre Hospitalier Universitaire, Limoges;</json:string></affiliations></json:item><json:item><name>C. Recher</name><affiliations><json:string>Service Hématologie, Centre Hospitalier Universitaire, Toulouse;</json:string></affiliations></json:item><json:item><name>M. Blanc</name><affiliations><json:string>Service Hématologie, Centre Hospitalier, Chambéry;</json:string></affiliations></json:item><json:item><name>T. Molina</name><affiliations><json:string>Service Anatomo-Pathologie, Hôtel Dieu, AP-HP, Paris;</json:string></affiliations></json:item><json:item><name>P. Lederlin</name><affiliations><json:string>Service Hématologie,</json:string></affiliations></json:item><json:item><name>B. Coiffier</name><affiliations><json:string>Service Hématologie, Hospices Civils, Lyon, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>aggressive non-Hodgkin’s lymphoma, central nervous system occurrence, risk factors, rituximab</value></json:item></subject><arkIstex>ark:/67375/HXZ-993BMG1R-B</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>other</json:string></originalGenre><abstract>Background: The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma. Patients and methods: We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol. Results: We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months. Conclusions: Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.</abstract><qualityIndicators><score>7.477</score><pdfWordCount>3041</pdfWordCount><pdfCharCount>19739</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>5</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>203</abstractWordCount><abstractCharCount>1343</abstractCharCount><keywordCount>1</keywordCount></qualityIndicators><title>Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</title><pmid><json:string>14679132</json:string></pmid><genre><json:string>other</json:string></genre><host><title>Annals of Oncology</title><language><json:string>unknown</json:string></language><issn><json:string>0923-7534</json:string></issn><eissn><json:string>1569-8041</json:string></eissn><publisherId><json:string>annonc</json:string></publisherId><volume>15</volume><issue>1</issue><pages><first>129</first><last>133</last></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Hematologic malignancies</value></json:item></subject></host><namedEntities><unitex><date><json:string>Between July 1998 and March 2000</json:string><json:string>1980</json:string><json:string>2004</json:string></date><geogName></geogName><orgName><json:string>Society for Medical Oncology</json:string><json:string>Revised European-American Lymphoma</json:string><json:string>World Health Organization</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Henri Becquerel</json:string><json:string>P. Feugier</json:string><json:string>D. Bordessoule</json:string><json:string>G. Marit</json:string><json:string>Initial</json:string><json:string>M. Blanc</json:string><json:string>T. Molina</json:string><json:string>H. Tilly</json:string><json:string>Henri Mondor</json:string><json:string>M. Macro</json:string><json:string>J. M. Virion</json:string><json:string>P. Lederlin</json:string><json:string>B. Coiffier</json:string><json:string>C. Haioun</json:string><json:string>C. Recher</json:string><json:string>Universitaire</json:string></persName><placeName><json:string>Toulouse</json:string><json:string>France</json:string><json:string>Limoges</json:string><json:string>Lyon</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[4]</json:string><json:string>[12]</json:string><json:string>[6]</json:string><json:string>[11]</json:string><json:string>Zinzani et al. [13]</json:string><json:string>[1]</json:string><json:string>[3]</json:string><json:string>[5]</json:string><json:string>[15]</json:string><json:string>[7]</json:string><json:string>[14]</json:string><json:string>[2]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-993BMG1R-B</json:string></ark><categories><wos><json:string>science</json:string><json:string>oncology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>oncology & carcinogenesis</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Oncology</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Hematology</json:string></scopus><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2004</publicationDate><copyrightDate>2004</copyrightDate><doi><json:string>10.1093/annonc/mdh013</json:string></doi><id>898B857B28F5AAACD7600687FEB4258B1CCFFFBD</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-993BMG1R-B/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-993BMG1R-B/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/HXZ-993BMG1R-B/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">Oxford University Press</publisher><availability><licence><p>European Society for Medical Oncology</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</p></availability><date>2004</date></publicationStmt><notesStmt><note type="other" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-7474895G-0">other</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note>Received 19 March 2003; revised 17 June 2003; accepted 20 August 2003</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</title><author xml:id="author-0000"><persName><forename type="first">P.</forename><surname>Feugier</surname></persName><affiliation>Service Hématologie,</affiliation></author><author xml:id="author-0001"><persName><forename type="first">J. M.</forename><surname>Virion</surname></persName><affiliation>Service Informatique Médicale, Hôpitaux de Brabois, Nancy;</affiliation></author><author xml:id="author-0002"><persName><forename type="first">H.</forename><surname>Tilly</surname></persName><affiliation>Centre Henri Becquerel, Rouen;</affiliation></author><author xml:id="author-0003"><persName><forename type="first">C.</forename><surname>Haioun</surname></persName><affiliation>Service Hématologie, Hôpital Henri Mondor, AP-HP, Créteil;</affiliation></author><author xml:id="author-0004"><persName><forename type="first">G.</forename><surname>Marit</surname></persName><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Bordeaux;</affiliation></author><author xml:id="author-0005"><persName><forename type="first">M.</forename><surname>Macro</surname></persName><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Caen;</affiliation></author><author xml:id="author-0006"><persName><forename type="first">D.</forename><surname>Bordessoule</surname></persName><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Limoges;</affiliation></author><author xml:id="author-0007"><persName><forename type="first">C.</forename><surname>Recher</surname></persName><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Toulouse;</affiliation></author><author xml:id="author-0008"><persName><forename type="first">M.</forename><surname>Blanc</surname></persName><affiliation>Service Hématologie, Centre Hospitalier, Chambéry;</affiliation></author><author xml:id="author-0009"><persName><forename type="first">T.</forename><surname>Molina</surname></persName><affiliation>Service Anatomo-Pathologie, Hôtel Dieu, AP-HP, Paris;</affiliation></author><author xml:id="author-0010"><persName><forename type="first">P.</forename><surname>Lederlin</surname></persName><affiliation>Service Hématologie,</affiliation></author><author xml:id="author-0011"><persName><forename type="first">B.</forename><surname>Coiffier</surname></persName><affiliation>Service Hématologie, Hospices Civils, Lyon, France</affiliation></author><idno type="istex">898B857B28F5AAACD7600687FEB4258B1CCFFFBD</idno><idno type="ark">ark:/67375/HXZ-993BMG1R-B</idno><idno type="DOI">10.1093/annonc/mdh013</idno><idno type="local">mdh013</idno></analytic><monogr><title level="j">Annals of Oncology</title><title level="j" type="abbrev">Ann Oncol</title><idno type="pISSN">0923-7534</idno><idno type="eISSN">1569-8041</idno><idno type="publisher-id">annonc</idno><idno type="PublisherID-hwp">annonc</idno><idno type="PublisherID-nlm-ta">Ann Oncol</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2004-01"></date><biblScope unit="volume">15</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="129">129</biblScope><biblScope unit="page" to="133">133</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2004</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Background: The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma. Patients and methods: We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol. Results: We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months. Conclusions: Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>aggressive non-Hodgkin’s lymphoma, central nervous system occurrence, risk factors, rituximab</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>Hematologic malignancies</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2004-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-993BMG1R-B/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="other" xml:lang="en">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">annonc</journal-id>
<journal-id journal-id-type="nlm-ta">Ann Oncol</journal-id>
<journal-id journal-id-type="publisher-id">annonc</journal-id>
<journal-title>Annals of Oncology</journal-title>
<abbrev-journal-title abbrev-type="publisher">Ann Oncol</abbrev-journal-title>
<issn pub-type="ppub">0923-7534</issn>
<issn pub-type="epub">1569-8041</issn>
<publisher>
<publisher-name>Oxford University Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="other">mdh013</article-id>
<article-id pub-id-type="doi">10.1093/annonc/mdh013</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Original articles</subject>
<subj-group>
<subject>Hematologic malignancies</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Feugier</surname>
<given-names>P.</given-names>
</name>
<xref rid="BABIFJDG">1</xref>
<xref rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Virion</surname>
<given-names>J. M.</given-names>
</name>
<xref rid="BABFJBFI">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tilly</surname>
<given-names>H.</given-names>
</name>
<xref rid="BABBAAFJ">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Haioun</surname>
<given-names>C.</given-names>
</name>
<xref rid="BABFEAJI">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Marit</surname>
<given-names>G.</given-names>
</name>
<xref rid="BABIDBJE">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Macro</surname>
<given-names>M.</given-names>
</name>
<xref rid="BABEIABF">6</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Bordessoule</surname>
<given-names>D.</given-names>
</name>
<xref rid="BABIIJDG">7</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Recher</surname>
<given-names>C.</given-names>
</name>
<xref rid="BABDBCFD">8</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Blanc</surname>
<given-names>M.</given-names>
</name>
<xref rid="BABEACBC">9</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Molina</surname>
<given-names>T.</given-names>
</name>
<xref rid="BABFFGDJ">10</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lederlin</surname>
<given-names>P.</given-names>
</name>
<xref rid="BABIFJDG">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Coiffier</surname>
<given-names>B.</given-names>
</name>
<xref rid="BABJHCHI">11</xref>
</contrib>
<aff><target target-type="aff" id="BABIFJDG"></target><label>1</label>Service Hématologie, <target target-type="aff" id="BABFJBFI"></target><label>2</label>Service Informatique Médicale, Hôpitaux de Brabois, Nancy; <target target-type="aff" id="BABBAAFJ"></target><label>3</label>Centre Henri Becquerel, Rouen; <target target-type="aff" id="BABFEAJI"></target><label>4</label>Service Hématologie, Hôpital Henri Mondor, AP-HP, Créteil; <target target-type="aff" id="BABIDBJE"></target><label>5</label>Service Hématologie, Centre Hospitalier Universitaire, Bordeaux; <target target-type="aff" id="BABEIABF"></target><label>6</label>Service Hématologie, Centre Hospitalier Universitaire, Caen; <target target-type="aff" id="BABIIJDG"></target><label>7</label>Service Hématologie, Centre Hospitalier Universitaire, Limoges; <target target-type="aff" id="BABDBCFD"></target><label>8</label>Service Hématologie, Centre Hospitalier Universitaire, Toulouse; <target target-type="aff" id="BABEACBC"></target><label>9</label>Service Hématologie, Centre Hospitalier, Chambéry; <target target-type="aff" id="BABFFGDJ"></target><label>10</label>Service Anatomo-Pathologie, Hôtel Dieu, AP-HP, Paris; <target target-type="aff" id="BABJHCHI"></target><label>11</label>Service Hématologie, Hospices Civils, Lyon, France</aff>
</contrib-group>
<pub-date pub-type="ppub">
<month>01</month>
<year>2004</year>
</pub-date>
<volume>15</volume>
<issue>1</issue>
<fpage>129</fpage>
<lpage>133</lpage>
<permissions>
<copyright-statement>European Society for Medical Oncology</copyright-statement>
<copyright-year>2004</copyright-year>
</permissions>
<abstract xml:lang="en">
<p>
<bold>Background:</bold>
</p>
<p>The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma.</p>
<p>
<bold>Patients and methods:</bold>
</p>
<p>We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol.</p>
<p>
<bold>Results:</bold>
</p>
<p>We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months.</p>
<p>
<bold>Conclusions:</bold>
</p>
<p>Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.</p>
</abstract>
<kwd-group kwd-group-type="KWD" xml:lang="en">
<kwd>aggressive non-Hodgkin’s lymphoma, central nervous system occurrence, risk factors, rituximab</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>hwp-legacy-fpage</meta-name>
<meta-value>129</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
<notes>
<p content-type="arthw-misc">Received 19 March 2003; revised 17 June 2003; accepted 20 August 2003</p>
</notes>
</front>
<body>
<sec>
<title>Introduction</title>
<p>Intrathecal prophylaxis of central nervous system (CNS) disease is a controversial issue in diffuse large-B-cell lymphoma. In such lymphomas, CNS occurrence [including development of CNS localization on therapy and after complete remission (CR) or partial remission (PR)] is an almost always fatal complication, but its incidence is not sufficiently high to warrant the use of CNS prophylaxis in all patients. Several studies have been published discussing the frequency of CNS occurrence in these lymphomas in order to identify patient subgroups for whom CNS prophylaxis might be of benefit. Comparison is hampered by the fact that most studies are based on retrospective analysis of heterogeneously treated patients.</p>
<p> The majority of non-Hodgkin’s lymphomas which involve the CNS are B-cell neoplasms which express CD20. The Groupe d’Etude des Lymphomes de l’Adulte (GELA) has recently shown that the addition of rituximab monoclonal antibody to the CHOP regimen (cyclophosphamide/doxorubicin/vincristine/prednisone) increases the CR rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma [<xref rid="MDH013C1">1</xref>]. The longer survival in the CHOP + rituximab group was due to a lower rate of disease progression during therapy and fewer relapses among patients who had a complete response. Rituximab is a chimeric anti-CD20 human IgG1 monoclonal antibody in which the CD20-binding region was derived by genetic engineering from a mouse monoclonal antibody. Little is known about its CNS diffusion.</p>
<p> We took advantage of this multicenter study to re-analyze data; the main objective was to assess if rituximab decreases the risk of secondary CNS occurrence. We also evaluate the influence of recognized CNS relapse risk factors in this homogeneous cohort of patients. Secondarily, we focused on the patients who achieved CR and developed isolated CNS relapse.</p>
</sec>
<sec>
<title>Patients and methods</title>
<sec>
<title>Patients</title>
<p>Between July 1998 and March 2000, the GELA undertook a study (named 98-5) to compare CHOP + rituximab with CHOP alone in 399 previously untreated elderly (60- to 80-year-old) patients with diffuse large-B-cell lymphoma that has been diagnosed according to the Revised European-American Lymphoma classification or the World Health Organization classification. The results have been previously published [<xref rid="MDH013C1">1</xref>]. Patients were required to have stage II, III or IV disease and a performance status of 0–2 according to the criteria of the Eastern Clinical Oncology Group. Eligible patients were randomly assigned to treatment with eight cycles of CHOP every 3 weeks or eight cycles of CHOP + rituximab 375 mg/m<sup>2</sup> given on day 1 of each cycle. All the patients enrolled in the 98-5 study gave written informed consent.</p>
<p> Prophylaxis of CNS disease was not part of the treatment protocol. All the patients (<italic>n</italic> = 399) were initially analyzed for the occurrence of CNS localization. Lumbar puncture and cerebrospinal fluid (CSF) cytopathological analysis were carried out (before randomization) in all the patients who entered the trial. Patients were not eligible if they had CNS involvement. However, we cannot formally exclude that subclinical CNS involvement might have existed in a proportion of patients at the time of diagnosis and before randomization, especially in patients who relapsed quickly after the diagnosis. Presumably, the randomization process would have allocated such patients equally between the two groups.</p>
</sec>
<sec>
<title>Diagnosis of CNS disease</title>
<p>The diagnosis of CNS localization, carried out after standardized staging evaluation, was based on the presence of malignant cells on cytocentrifuge preparations of spinal fluid in seven cases and on brain biopsy in two cases. In 10 cases, the diagnosis of CNS disease was based on symptoms and radiological findings and in one case it was based on clinical symptoms only.</p>
</sec>
<sec>
<title>Statistical methods</title>
<p>Comparisons among groups were analyzed by the chi-square test and the Fisher exact test when appropriate. In order to determine the most appropriate factor predicting for CNS occurrences, a logistic regression analysis was carried out to assess the effect of pretreatment prognostic factors [age, sex, number of extranodal sites, β2-microglobulin level, serum albumin level, B symptoms (weight loss, fever and night sweats) and type of treatment]. A second multivariate logistic regression analysis was carried out including the age-adjusted International Prognostic Index (aa IPI) score. Survival curves and actuarial risk of patients with CNS occurrence was calculated by the Kaplan–Meier method.</p>
</sec>
</sec>
<sec>
<title>Results</title>
<sec>
<title>Patients</title>
<p>Initial characteristics of the 399 enrolled patients in the study as well as the response to treatment with CHOP or CHOP + rituximab are given in Table <xref rid="MDH013TB1">1</xref> (adapted from [<xref rid="MDH013C1">1</xref>]). The median age of the patients was 69 years. A total of 276 patients out of 399 patients (69.2%) achieved a CR following treatment: 63% with CHOP only and 76% in the CHOP + rituximab group. With a median follow-up of 24 months, 20 CNS occurrences were observed (Table <xref rid="MDH013TB2">2</xref>). Actuarial risk of CNS occurrence at 1 year was 5.34% (95% confidence interval 2.99% to 7.69%). The median time between diagnosis and CNS occurrence was 6 months whatever the treatment arm. CNS occurrences developed in 20 patients, these being 12 on therapy, four after PR and four patients following CR (CR or unconfirmed CR); of the latter, in three patients, the CNS was the only site of relapse whereas in one patient, CNS disease was part of systemic relapse. A central pathology review was conducted in this protocol leading to 49 diagnoses of non-diffuse large-B-cell lymphoma. Among the 20 patients with CNS occurrence, four diagnoses were modified: three as mantle-cell lymphoma (MCL) (blastoid histological subtype) and one as follicular lymphoma (two in the CHOP group and two in the CHOP + rituxumab group). The high number of CNS occurrences in MCL is not surprising, especially in the blastoid subtype [<xref rid="MDH013C2">2</xref>].</p>
<p> Patients with reviewed diffuse lymphoma diagnosis were equally distributed in each treatment group (eight in each arm). Among these 16 patients, nine were histologically or cytologically documented and seven were not (four in the CHOP + rituximab group and three in the CHOP group). A variety of clinical and radiological symptoms led to the diagnosis of CNS occurrence; they included intracranial hypertension (<italic>n</italic> = 6), cranial nerve palsy (<italic>n</italic> = 1) and/or hemiplegia (<italic>n</italic> = 1). Brain parenchymal involvement (parenchymal tumors with edema and mass effect) was diagnosed in six out of the seven patients.</p>
</sec>
<sec>
<title>Risk factors for CNS occurrence</title>
<p>We analyzed whether the risk of CNS occurrence was related to the treatment group (CHOP versus CHOP + rituximab) as well as the usual risk factors described in CNS relapse. As shown in Table <xref rid="MDH013TB3">3</xref> and in univariate analysis, an increased risk of CNS occurrence was associated with an advanced stage (<italic>P</italic> = 0.014), an elevated lactate dehydrogenase (LDH) level (<italic>P</italic> = 0.005), a poor performance status (<italic>P</italic> = 0.018) and an increased aa IPI (<italic>P</italic> <0.001). The presence of more than one extranodal site and the localization of extranodal sites as well as the age, sex and B symptoms were not related to the risk of CNS occurrence. Treatment group did not influence the risk of CNS localization. We observed 11 CNS occurrences in the CHOP + rituximab group and nine in the CHOP group without differences between patients in CR (two in both groups), PR (three in the CHOP + rituximab group, one in the CHOP group) or developing CNS localization on therapy (six in both groups). In a first multivariate analysis, all the parameters found to be significant (<italic>P</italic> <0.10), except aa IPI, were introduced in a logistic regression model. Poor performance status and elevated LDH were the two independent predictive factors of CNS occurrence. In a second logistic regression analysis including aa IPI, aa IPI was identified as the only independent factor associated with a higher risk of CNS occurrence (aa IPI 0 and 1 versus 2 and 3: odds ratio = 3.05 and confidence limits 1.58–5.88).</p>
<p> Exclusion of non-diffuse lymphoma or non-cytologically or histologically documented patients did not change our conclusion, i.e. rituximab does not influence CNS occurrence.</p>
</sec>
<sec>
<title>Treatment of CNS occurrence and outcome</title>
<p>CNS occurrence has a poor prognosis especially when observed on therapy or after PR and if it is part of systemic relapse. Treatment of the 20 patients with CNS occurrence was conducted according to each center’s policy and therefore was heterogeneous. A total of 18 of 20 patients received a variable number of intrathecal injections of methotrexate, ara-C and dexamethasone associated with a systemic chemotherapy: high-dose methotrexate, COP-COPADM (including prednisone/vincristine/cyclophosphamide/ara-C/methotrexate/doxorubicin) [<xref rid="MDH013C3">3</xref>], VIM2-ARAC (including mitoxantrone/etoposide/ifosfamide/ara-C) [<xref rid="MDH013C4">4</xref>] or DHAP (including mitoxantrone/etoposide/ifosfamide/ara-C) [<xref rid="MDH013C5">5</xref>]. Four patients presenting with cranial nerve palsies or intraparenchymal lesions in the brain or epidural lesion were given additional radiotherapy (two associated with chemotherapy). Only one patient presented an epidural tumor but was considered as CNS occurrence since he had associated leptomeningeal disease. Finally, two patients did not receive any treatment because of diffuse relapse and poor performance status. At the time of analysis, only three of 20 patients were alive: two presented as isolated CNS relapse after CR, one after PR (with a 20-month follow-up). All the patients with relapse on therapy died within 4 months whatever the administered treatment.</p>
</sec>
<sec>
<title>Isolated CNS relapse following CR</title>
<p>The CNS was the only site of relapse in only three patients in CR (three of 276 = 1.1%). All three patients received systemic chemotherapy (one was treated with high-dose methotrexate and two with COP-COPADM regimen) associated with a variable number of intrathecal injections of ara-C, methotrexate and dexamethasone. All the patients attained a second CR. Two patients were alive in second CR with a follow-up of 20 and 34 months and one died 4 months after systemic recurrence.</p>
</sec>
</sec>
<sec>
<title>Discussion</title>
<p>Here we report secondary CNS occurrence in an homogeneous population of 399 elderly patients with aggressive diffuse lymphoma prospectively treated with CHOP or CHOP + rituximab. With a median follow-up of 24 months, 20 CNS localizations were observed, 11 in the CHOP + rituximab and nine in the CHOP group. According to the univariate and multivariate analysis, rituximab (at the dose of 375 mg/m<sup>2</sup> on day 1 of each eight 3-week CHOP courses) did not influence the risk of CNS occurrence. Rituximab has been demonstrated to be effective in the treatment of non-Hodgkin’s B-cell lymphoma. <italic>In vitro</italic> studies have shown that direct complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and apoptosis are important in the rituximab-induced killing of lymphoma cells. Initial pharmacokinetic studies have shown that an intact blood–brain barrier restricts the entry of rituximab into the CNS [<xref rid="MDH013C6">6</xref>]. After intravenous administration, rituximab can be reproducibly measured in the CSF in patients with primary CNS lymphoma; however, the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin’s lymphoma [<xref rid="MDH013C7">7</xref>]. Our data supported such a conclusion, since CNS relapse is not influenced by rituximab administration.</p>
<p> Most reported studies include isolated and diffuse localizations, occurring on therapy or after PR or CR has been obtained. In such series of patients, the overall incidence of CNS localizations is around 5%, similar to that which we observed. We show that the risk of CNS localization is related to the aa IPI; patients with a higher index have higher rates of CNS occurrence, confirming reported studies showing that secondary CNS occurrence is related to IPI or aa IPI (if analyzed) or to the factors forming part of it [<xref rid="MDH013C8">8</xref>–<xref rid="MDH013C10">10</xref>]. However, it is admitted that CNS localization associated with systemic relapse is an expression of end-stage disease and is usually refractory to all types of treatment. Indeed, in our population, all these patients died within 4 months. On the contrary, isolated CNS localization occurring after CR may be potentially treatable. In our series, we observed three (1.1%) isolated relapses among 276 CR patients. The incidence and risk factors for isolated CNS relapse have been assessed in recent studies of homogeneous and prospectively treated diffuse lymphoma patients who achieved CR and who did (ACVBP regimen) [<xref rid="MDH013C11">11</xref>] or did not (CHOP regimen) [<xref rid="MDH013C12">12</xref>] receive intrathecal chemoprophylaxis. Similar isolated CNS incidence was observed after CR (1% and 1.6%, respectively) and IPI was also identified as a unique independent risk factor for isolated CNS relapse in multivariate analysis. In contrast, Zinzani et al. [<xref rid="MDH013C13">13</xref>] reported a higher incidence (5.2%) of isolated CNS occurrence in an unselected series of 175 patients with non-lymphoblastic, non-Burkitt aggressive lymphoma in CR following an anthracycline-containing regimen without intrathecal CNS prophylaxis.</p>
<p> The ACVBP regimen (four cycles every 3 weeks of doxorubicin/cyclophosphamide/vindesine/bleomycin/prednisone with four intrathecal injections of methotrexate followed by sequential consolidation therapy including high-dose methotrexate, ifosfamide, etoposide and ara-C) has been used by the GELA since 1980. The 93-5 GELA study compared ACVBP with the standard CHOP regimen in elderly patients [<xref rid="MDH013C14">14</xref>]. The ACVBP regimen was found to be associated with longer event-free survival and prolonged survival. CNS occurrences were more frequent in the CHOP group (26 of 312 versus nine of 323) but the majority occurred on therapy (21 in the CHOP group versus only six in the ACVBP group); the number of isolated CNS relapses was similar in the two groups (two of 172 in the CHOP versus two of 177 in the ACVBP group). These data suggest that the risk of CNS disease is related to the risk of systemic recurrence. Administration of more intensive induction chemotherapy (ACVBP) as well as use of drugs crossing the blood–brain barrier (methotrexate, VP16 and aracytine) could explain the lower number of systemic and isolated CNS occurrences. The higher number of secondary CNS occurrences (26 of 312 = 8%) in the 93-5 CHOP arm compared with the 98-5 study could be partially related to the number of T-cell lymphomas (15%) included in the 93-5 study as well as the absence of aa IPI = 0 patients.</p>
<p> Our data show that rituximab (at the dose of 375 mg/m<sup>2</sup> on day 1 of each eight 3-week CHOP courses) did not influence the risk of secondary CNS occurrence in elderly patients with diffuse large-B-cell lymphoma, possibly because of low rituximab diffusion across the blood–brain barrier. Direct intrathecal administration of rituximab might overcome this problem, since preliminary pharmacokinetic studies in the monkey suggest that such administration results in an initially high concentration before distribution into the CSF without toxicity [<xref rid="MDH013C15">15</xref>]. We also confirmed other reported studies showing that CNS occurrence is related to aa IPI as well as very poor prognosis of relapses occurring on therapy or in a systemic disease. Our observations suggest that the risk of secondary CNS occurrence is related to disease control, since most of the patients developed CNS disease either on therapy or in PR. It can be hypothesized that more effective systemic treatment could decrease the number of patients with CNS disease occurring on therapy. This strategy has been included in the ongoing 01-5B trial designed for patients aged from 60 to 65 years comparing the CHOP + rituximab with an ACVBP + rituximab regimen.</p>
</sec>
<sec>
<title></title>
<p>
<fn id="FN1" xml:lang="en">
<label>*</label>
<p><italic>Correspondence to:</italic> Dr P. Feugier, Hématologie Adulte-Hôpitaux de Brabois, Rue du Morvan, 54511 Vandoeuvre, France. Tel: +33-3-83153282; Fax: +33-3-83153558; E-mail: <ext-link xlink:href="p.feugier@chu-nancy.fr" ext-link-type="email">p.feugier@chu-nancy.fr</ext-link></p>
</fn>
<table-wrap id="MDH013TB1">
<label>
<bold>Table 1.</bold>
</label>
<caption>
<p> 98-5 study: patient characteristics</p>
</caption>
<table>
<tbody align="left" valign="bottom">
<tr>
<td valign="bottom" rowspan="1">Characteristic</td>
<td valign="bottom" rowspan="1">CHOP + rituximab (<italic>n</italic> = 202)</td>
<td valign="bottom" rowspan="1">CHOP (<italic>n</italic> = 197)</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Age (years)</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> ≤69</td>
<td valign="bottom" rowspan="1">101</td>
<td valign="bottom" rowspan="1">110</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >70</td>
<td valign="bottom" rowspan="1">101</td>
<td valign="bottom" rowspan="1"> 87</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Male sex</td>
<td valign="bottom" rowspan="1"> 92</td>
<td valign="bottom" rowspan="1">107</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Performance status</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 67</td>
<td valign="bottom" rowspan="1"> 70</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 90</td>
<td valign="bottom" rowspan="1"> 94</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >1</td>
<td valign="bottom" rowspan="1"> 45</td>
<td valign="bottom" rowspan="1"> 33</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">B symptoms</td>
<td valign="bottom" rowspan="1"> 78</td>
<td valign="bottom" rowspan="1"> 70</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Stage</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> I</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 1</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> II</td>
<td valign="bottom" rowspan="1"> 41</td>
<td valign="bottom" rowspan="1"> 39</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> III</td>
<td valign="bottom" rowspan="1"> 33</td>
<td valign="bottom" rowspan="1"> 29</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> IV</td>
<td valign="bottom" rowspan="1">128</td>
<td valign="bottom" rowspan="1">128</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Number of extranodal sites</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 46</td>
<td valign="bottom" rowspan="1"> 44</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 95</td>
<td valign="bottom" rowspan="1">102</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> ≥2</td>
<td valign="bottom" rowspan="1"> 61</td>
<td valign="bottom" rowspan="1"> 51</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Bone marrow involvement</td>
<td valign="bottom" rowspan="1"> 56</td>
<td valign="bottom" rowspan="1"> 55</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Elevated lactate dehydrogenase </td>
<td valign="bottom" rowspan="1">131</td>
<td valign="bottom" rowspan="1">132</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Age-adjusted IPI</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 20</td>
<td valign="bottom" rowspan="1"> 21</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 61</td>
<td valign="bottom" rowspan="1"> 56</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 2</td>
<td valign="bottom" rowspan="1">87</td>
<td valign="bottom" rowspan="1"> 94</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1">34</td>
<td valign="bottom" rowspan="1"> 26</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Response</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Complete + unconfirmed complete</td>
<td valign="bottom" rowspan="1">152</td>
<td valign="bottom" rowspan="1">124</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Partial</td>
<td valign="bottom" rowspan="1">15</td>
<td valign="bottom" rowspan="1"> 11</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Stable disease</td>
<td valign="bottom" rowspan="1">2</td>
<td valign="bottom" rowspan="1"> 1</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Progressive disease</td>
<td valign="bottom" rowspan="1">19</td>
<td valign="bottom" rowspan="1"> 43</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Death without progression</td>
<td valign="bottom" rowspan="1">12</td>
<td valign="bottom" rowspan="1"> 11</td>
</tr>
<tr>
<td content-type="rowsep" valign="bottom" rowspan="1"> Could not be assessed</td>
<td content-type="rowsep" valign="bottom" rowspan="1">2</td>
<td content-type="rowsep" valign="bottom" rowspan="1"> 7</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; IPI, International Prognostic Index.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="MDH013TB2">
<label>
<bold>Table 2.</bold>
</label>
<caption>
<p> Secondary central nervous system (CNS) occurrence: patients characteristics</p>
</caption>
<table>
<tbody align="left" valign="bottom">
<tr>
<td content-type="rowsep" valign="bottom" rowspan="1">Characteristic</td>
<td content-type="rowsep" valign="bottom" rowspan="1">CHOP + rituximab (<italic>n</italic> = 11)</td>
<td content-type="rowsep" valign="bottom" rowspan="1">CHOP (<italic>n</italic> = 9)</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Age (years)</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> ≤69</td>
<td valign="bottom" rowspan="1"> 8</td>
<td valign="bottom" rowspan="1">7</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >70</td>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1">2</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Male sex</td>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1">6</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Performance status</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 2</td>
<td valign="bottom" rowspan="1">1</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 5</td>
<td valign="bottom" rowspan="1">5</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >1</td>
<td valign="bottom" rowspan="1"> 4</td>
<td valign="bottom" rowspan="1">3</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">B symptoms</td>
<td valign="bottom" rowspan="1"> 5</td>
<td valign="bottom" rowspan="1">5</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Stage</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> I</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1">0</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> II</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1">1</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> III</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1">1</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> IV</td>
<td valign="bottom" rowspan="1">11</td>
<td valign="bottom" rowspan="1">7</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Number of extranodal sites</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1">1</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1">2</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> ≥2</td>
<td valign="bottom" rowspan="1"> 8</td>
<td valign="bottom" rowspan="1">6</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Elevated lactate dehydrogenase</td>
<td valign="bottom" rowspan="1">10</td>
<td valign="bottom" rowspan="1">9</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Age-adjusted IPI</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1">0</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1">0</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 2</td>
<td valign="bottom" rowspan="1"> 8</td>
<td valign="bottom" rowspan="1">7</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1">2</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Revised histological diagnosis</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Aggressive lymphoma</td>
<td valign="bottom" rowspan="1"> 8</td>
<td valign="bottom" rowspan="1">8</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Mantle-cell lymphoma</td>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1">0</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Follicular lymphoma</td>
<td valign="bottom" rowspan="1">0</td>
<td valign="bottom" rowspan="1">3</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">CNS occurrence diagnosis</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Cytology/histology</td>
<td valign="bottom" rowspan="1">5</td>
<td valign="bottom" rowspan="1">5</td>
</tr>
<tr>
<td content-type="rowsep" valign="bottom" rowspan="1"> Clinical/radiological findings</td>
<td content-type="rowsep" valign="bottom" rowspan="1">4</td>
<td content-type="rowsep" valign="bottom" rowspan="1">6</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; IPI, International Prognostic Index.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="MDH013TB3">
<label>
<bold>Table 3.</bold>
</label>
<caption>
<p> Risk factors analysis for central nervous system (CNS) occurrence</p>
</caption>
<table>
<tbody align="left" valign="bottom">
<tr>
<td content-type="rowsep" valign="bottom" rowspan="1">Characteristics</td>
<td content-type="rowsep" valign="bottom" rowspan="1">No CNS occurrence</td>
<td content-type="rowsep" valign="bottom" rowspan="1">CNS occurrence</td>
<td content-type="rowsep" valign="bottom" rowspan="1"><italic>P</italic> value</td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Age (years)</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.11</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> ≤65</td>
<td valign="bottom" rowspan="1"> 88</td>
<td valign="bottom" rowspan="1"> 4</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >65 and ≤70</td>
<td valign="bottom" rowspan="1">109</td>
<td valign="bottom" rowspan="1">10</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >70</td>
<td valign="bottom" rowspan="1">182</td>
<td valign="bottom" rowspan="1"> 6</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Sex</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.65</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Male</td>
<td valign="bottom" rowspan="1">190</td>
<td valign="bottom" rowspan="1"> 9</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Female</td>
<td valign="bottom" rowspan="1">189</td>
<td valign="bottom" rowspan="1">11</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Lactate dehydrogenase</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.005</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Elevated</td>
<td valign="bottom" rowspan="1">244</td>
<td valign="bottom" rowspan="1">19</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Normal</td>
<td valign="bottom" rowspan="1">135</td>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Stage</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.014</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> I</td>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> II</td>
<td valign="bottom" rowspan="1"> 79</td>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> III</td>
<td valign="bottom" rowspan="1"> 61</td>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> IV</td>
<td valign="bottom" rowspan="1">238</td>
<td valign="bottom" rowspan="1">18</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">B symptoms</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.22</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> Yes</td>
<td valign="bottom" rowspan="1">138</td>
<td valign="bottom" rowspan="1">10</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> No</td>
<td valign="bottom" rowspan="1">241</td>
<td valign="bottom" rowspan="1">10</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Performance status</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.018</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0–1</td>
<td valign="bottom" rowspan="1">309</td>
<td valign="bottom" rowspan="1">12</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >1</td>
<td valign="bottom" rowspan="1"> 70</td>
<td valign="bottom" rowspan="1"> 8</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Extra nodal site<bold>s</bold></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.246</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0–1</td>
<td valign="bottom" rowspan="1">183</td>
<td valign="bottom" rowspan="1"> 7</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> >1</td>
<td valign="bottom" rowspan="1">196</td>
<td valign="bottom" rowspan="1">13</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Age-adjusted IPI</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"><0.001</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"> 41</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 1</td>
<td valign="bottom" rowspan="1">117</td>
<td valign="bottom" rowspan="1"> 0</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 2</td>
<td valign="bottom" rowspan="1">166</td>
<td valign="bottom" rowspan="1">15</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> 3</td>
<td valign="bottom" rowspan="1"> 55</td>
<td valign="bottom" rowspan="1"> 5</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td valign="bottom" rowspan="1">Treatment</td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"></td>
<td valign="bottom" rowspan="1"> 0.688</td>
</tr>
<tr>
<td valign="bottom" rowspan="1"> CHOP</td>
<td valign="bottom" rowspan="1">188</td>
<td valign="bottom" rowspan="1"> 9</td>
<td valign="bottom" rowspan="1"></td>
</tr>
<tr>
<td content-type="rowsep" valign="bottom" rowspan="1"> CHOP + rituximab</td>
<td content-type="rowsep" valign="bottom" rowspan="1">191</td>
<td content-type="rowsep" valign="bottom" rowspan="1">11</td>
<td content-type="rowsep" valign="bottom" rowspan="1"></td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>IPI, International Prognostic Index.</p>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
</body>
<back>
<ref-list>
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<label>1.</label>
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</article>
</istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab</title></titleInfo><name type="personal"><namePart type="given">P.</namePart><namePart type="family">Feugier</namePart><affiliation>Service Hématologie,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J. M.</namePart><namePart type="family">Virion</namePart><affiliation>Service Informatique Médicale, Hôpitaux de Brabois, Nancy;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H.</namePart><namePart type="family">Tilly</namePart><affiliation>Centre Henri Becquerel, Rouen;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C.</namePart><namePart type="family">Haioun</namePart><affiliation>Service Hématologie, Hôpital Henri Mondor, AP-HP, Créteil;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G.</namePart><namePart type="family">Marit</namePart><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Bordeaux;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M.</namePart><namePart type="family">Macro</namePart><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Caen;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">D.</namePart><namePart type="family">Bordessoule</namePart><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Limoges;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C.</namePart><namePart type="family">Recher</namePart><affiliation>Service Hématologie, Centre Hospitalier Universitaire, Toulouse;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M.</namePart><namePart type="family">Blanc</namePart><affiliation>Service Hématologie, Centre Hospitalier, Chambéry;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">T.</namePart><namePart type="family">Molina</namePart><affiliation>Service Anatomo-Pathologie, Hôtel Dieu, AP-HP, Paris;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P.</namePart><namePart type="family">Lederlin</namePart><affiliation>Service Hématologie,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B.</namePart><namePart type="family">Coiffier</namePart><affiliation>Service Hématologie, Hospices Civils, Lyon, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="other" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-7474895G-0">other</genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2004-01</dateIssued><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Background: The incidence of secondary central nervous system (CNS) occurrences in diffuse large-B-cell lymphoma is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The addition of rituximab increases the complete response rate and prolongs event-free and overall survival in elderly patients with such lymphoma. Patients and methods: We analyzed a cohort of 399 elderly patients with lymphoma prospectively treated with eight cycles of CHOP with or without rituximab in order to assess if rituximab decreases the risk of CNS localization. Prophylaxis of CNS disease was not part of the treatment protocol. Results: We observed 20 CNS occurrences: 12 on therapy, four after partial remission and four following complete remission. In three patients, the CNS was the only site of relapse. In a multivariate analysis, increased age-adjusted International Prognostic Index (IPI) was the only independent predictive factor of CNS recurrence. Only three of 20 patients are alive with a follow-up of 24 months. Conclusions: Rituximab did not influence the risk of CNS occurrence, possibly because of low rituximab diffusion. Direct intrathecal administration of rituximab could overcome this problem. We also confirmed that CNS occurrence is related to IPI as well as very poor prognosis of relapses occurring on therapy.</abstract><note>Received 19 March 2003; revised 17 June 2003; accepted 20 August 2003</note><subject lang="en"><genre>KWD</genre><topic>aggressive non-Hodgkin’s lymphoma, central nervous system occurrence, risk factors, rituximab</topic></subject><relatedItem type="host"><titleInfo><title>Annals of Oncology</title></titleInfo><titleInfo type="abbreviated"><title>Ann Oncol</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><subject><topic>Hematologic malignancies</topic></subject><identifier type="ISSN">0923-7534</identifier><identifier type="eISSN">1569-8041</identifier><identifier type="PublisherID">annonc</identifier><identifier type="PublisherID-hwp">annonc</identifier><identifier type="PublisherID-nlm-ta">Ann Oncol</identifier><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>15</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>129</start><end>133</end></extent></part></relatedItem><identifier type="istex">898B857B28F5AAACD7600687FEB4258B1CCFFFBD</identifier><identifier type="DOI">10.1093/annonc/mdh013</identifier><identifier type="local">mdh013</identifier><accessCondition type="use and reproduction" contentType="copyright">European Society for Medical Oncology</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>European Society for Medical Oncology</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-993BMG1R-B/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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