Rituximab Anticorpo Monoclonal - anti-CD20

Ttulo: Origem: Autor: Especialidade: Data de criao: Data da ltima atualizao: Data para nova atualizao: Cdigos AMB: Cdigos CBHPM: CID-10 envolvidos: Situao (consagrada/em estudo): Rituximab anticorpo monoclonal - anti-CD20 Unimed SC Dr. Alvaro Koenig Oncologia; hematologia; auditoria mdica Outubro/2005

2.01.04.26-0; 2.01.04.27-8 C82.0; C82.2; C92 Consagrada

OBJETIVO Analisar a efetividade do rituximab no tratamento de neoplasias hematolgicas.

PROFISSIONAL ALVO Oncologistas, hematologistas, auditores mdicos FUNDAMENTAO O primeiro anticorpo monoclonal anti-CD20 foi desenvolvido por Press et al. e mostrou pequena atividade clnica (Press 1987). Os resultados mais promissores se deram com a introduo de rituximab (IDEC-C2B8, Rituxan, Mabthera) anticorpo quimrico monoclonal anti-CD20. Anticorpos monoclonais quimricos so produzidos por engenharia gentica e possuem uma regio constante de um anticorpo IgG e uma regio varivel de um anticorpo murino. Uma grande vantagem dos anticorpos monoclonais quimricos sobre os murinos o aumentado mecanismo efetor do organismo por apresentar ligao aumentada das clulas efetoras humanas ao complemento. Rituximab mostrou resultados promissores com ao em diferentes subgrupos de linfomas de clulas B, especialmente em linfoma folicular em recidiva (Maloney 1997; McLaughlin 1998). Diferentemente da quimiooterapia regular, a imunoterapia um tratamento altamente direcionado. Rituximab apresenta vrios mecanismos de destruio de clulas tumorais. O anticorpo reage com o antgeno CD-20 dos linfcitos B atravs de vriios mecanismos, como citotoxicidade complemento-dependente, citotoxicidade celular complemento-dependente e apoptose (Reff 1994). Alm disto, o rituximab sensibiliza as linhagens droga-resistentes de linfomas de clulas B para o efeito citotxico de outros agentes quimioterpicos(Demidem 1995).

No entanto, o rituximab no parece ser efetivo para todas as linhagens de linfomas no-Hodgkin, alm de ser uma droga bastante dispendiosa, o que requer que seu uso seja direcionado exclusivamente para as situaes clnicas nas quais se consiga demonstrar uma relao custo/efetividade favorvel.

METODOLOGIA Fonte de dados Foram pesquisados as bases de dados Pubmed, Dare e biblioteca Cochrane. Palavras-Chave Rituximab Desenhos dos Estudos Buscados Metanlises, ensaios clnicos randomizados de fase III, revises sistemticas e anlises de custo-efetividade.

Populao Includa e Excluda Foram avaliados os estudos que abrangessem populao masculina e/ou feminina, adulta, com neoplasia hematolgica.

RESUMO DAS PUBLICAES SELECIONADAS Foram selecionadas 17 referncias Metanlises: 0 Reviso sistematizada: 1 Ensaio clnico randomizado: 13 Anlise de custo-utilidade : 1 Ensaios clnicos com controles histricos: 2

Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the RCHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. As taxas de Sobrevida geral, livre de eventos, livre da doena e livre de progresso aps 5 anos so significativamente maiores no grupo com a combinao def R-CHOP (P = .00002, P < .00001, P < .00031, and P < .0073) respectivamente.

Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, Sebban C, Berger F, Bosly A, Morel P, Tilly H, Bouabdallah R, Reyes F, Gaulard P, Coiffier B. Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003 Jun 1;101(11):4279-84 Aps seguimento de 2 anos, R-CHOP foi associado significativamente com melhor sobrevida que CHOP em pacientes bcl-2+ (67% +/- 9% versus 48% +/- 11%, P =.004).(NNT= 52). Em pacientes bcl-2- no houve diferena significativa (72% +/- 12% versus 67% +/- 14%, P =.6). R-CHOP foi associado com significativamente melhor sobrevida livre da doena que CHOP em pacientes bcl-2+ (58% +/- 10% versus 32% +/- 10%, P <.001)(NNT= 34) mas no em pacientes bcl-2- (60% +/- 13% versus 40% +/- 15%, P =.13) Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med. 2002 Jan 24;346(4):235-42.. Aps 2 anos de seguimento os tempos de sobrevida geral e livre de eventos foi significamente maior no grupo CHOP-rituximab (P<0.001 e P=0.007) Hornberger JC, Best JH. Cost utility in the United States of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone for the treatment of elderly patients with diffuse large B-cell lymphoma. Cancer. 2005 Apr 15;103(8):1644-51. Aps 5 anos R-CHOP prolonga o tempo de sobrevida em 1.04 anos e, comparado com CHOP, pode ser custo-efetivo em pacientes idosos com linfomas difuso de clulas B grandes Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005 Mar 20;23(9):1984-92. No foram observadas diferenas significativas na sobrevida livre da doena e livre de progresso entres os grupos R-CHOP e CHOP Ghielmini M, Schmitz SF, Cogliatti S, Bertoni F, Waltzer U, Fey MF, Betticher DC, Schefer H, Pichert G, Stahel R, Ketterer N, Bargetzi M, Cerny T; Swiss Group for Clinical Cancer Research. Effect of single-agent

rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005 Feb 1;23(4):705-11. Resposta clnica ps-induo foi de 27% com 2% de remisso completa. Aps 29 meses no houve diferena na taxa e durao da resposta e na sobrevida livre de eventos entre os grupos com e sem tratamento complementar. Obs.: No compara com tratamento padro Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71 No grupo todo(folicular e manto) o brao R-FCM teve sobrevida geral e livre de progresso significativamente superior (PFS; P = .0381) and overall survival (OS; P = .0030). Analise de subgrupo: No MCL a sobrevida geral(overall survival) foi significativamente maior(P = .0042). Forstpointner R, Hanel A, Repp R, Hermann S, Metzner B, Pott C, Hartmann F, Rothmann F, Bock HP, Wandt H, Unterhalt M, Hiddemann W. Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group] Dtsch Med Wochenschr. 2002 Oct 25;127(43):2253-8. Analisa apenas taxas de resposta geral(R-FCM 83% vs FCM 58%), e remisso completa (CR: 35 % vs. 13 %). Obs: Sem analise de sobrevida Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, SolalCeligny P, Offner F, Walewski J, Raposo J, Jack A, Smith P . CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. Resposta geral e completa foi de 81% e 41% no grupo R-CVP versus 57% e 10% no CVP (P < .0001). Aps 30 meses de seguimento o tempo p/ progresso foi maior no grupo R-CVP ( 32 x 15 meses ; P < .0001). Tempo medio p/ falncia tratamento foi > no grupo R-CVP (27 x 7 meses) (P < .0001). Sem anlise de sobrevida Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs

survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. R-FCM mostrou remisso completa e parcial de 33% e 45%, comparada com 13% e 45% no CFM( P = .01). No grupo todo o brao R-FCM apresentou sobrevida geral e livre de progresso significativamente superiores ( P = .0381 e P = .0030 respectivamente) Anlise de subgrupo: Nos pacientes com linfoma folicular a sobrevida livre de progresso foi superior no grupo R-FCM (P = .0139) Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani MFludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61 Seguimento de 19 meses( 9 a 37 ) no mostrou diferenas entre os 4 braos do estudo em sobrevida geral e livre de progresso Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny TProlonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):441623. Taxa de resposta foi 67% em pac sem tratamento e 46% em pac com trat prvio (P <.01). Aps 35 meses de seguimento a sobrevida livre de eventos foi de 12 meses no grupo no-tratado e 23 meses no grupo tratado(P 0,02) Em pacientes sem QT prvia (19 vs 36 meses; P =.009) e em pacientes que responderam induo (16 vs 36 meses; P =.004). Obs.: No houve comparao com o tratamento padro Forstpointner R, Hanel A, Repp R, Hermann S, Metzner B, Pott C, Hartmann F, Rothmann F, Bock HP, Wandt H, Unterhalt M, Hiddemann W. Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group] Dtsch Med Wochenschr. 2002 Oct 25;127(43):2253-8. Taxa de resposta global 83 % no R-CFM vs 58%no grupo FCM (Remisso completa: 35 % vs. 13 %). Obs.: No foi realizada anlise da sobrevida. Trabalho atualizado em . Blood. 2004 Nov 15;104(10):3064-71

Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin's lymphoma: a systematic review and economic evaluation. Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, Davenport C. Health Technology Assessment 2002; 6(3): 1-85. Taxa de resposta global variou de 39 a 48%. As taxas de resposta completa variaram de 3 a 6%. A durao da resposta foi de apenas 5,9 meses. Tempo p/ progresso para os que responderam ao tratamento foi de 8,1 meses. Sem anlise de sobrevida e qualidade de vida. Como tratamento complementar o rituximab custaria 17.4 milhes/ano ao sistema de sade ingls. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14 Aps seguimento mdio de 23 meses a durao mdia de resposta e a sobrevida foram semelhantes nos 2 grupos. Estudo de fase II

Khouri IF, Saliba RM, Hosing C, Okoroji GJ, Acholonu S, Anderlini P, Couriel D, De Lima M, Donato ML, Fayad L, Giralt S, Jones R, Korbling M, Maadani F, Manning JT, Pro B, Shpall E, Younes A, McLaughlin P, Champlin RE. Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2005 Apr 1;23(10):2240-7. Sobrevida geral aps 2 anos foi de 80% (95% CI, 65% a 89%) para o grupo do estudo e 53% (95% CI, 34% a 69%) para o grupo controle (P = .002). Sobrevida livre de doena foi de 67% (95% CI, 51% a 79%) para o grupo do estudo e 43% (95% CI, 26% a 60%) para o controle histrico (P = .004). Resultados sujeitos a vieses pela comparao com controles histricos Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005 Sep 1;106(5):1538-43. Aps seguimento mdio de 137 semanas o tempo para progresso, a sobrevida geral e livre de progresso foi semelhante nos 2 grupos.

CONCLUSO A. Benefcio definido: 1. Em linfoma difuso de clulas B grandes a adio de rituximab ao esquema habitual(CHOP) aumenta significativamente as taxas de sobrevida em idosos acima de 60 anos(Event-free, progression-free , disease-free e overall survival), especialmente nos pacientes com expresso da protena bcl+ B. Benefcio potencial 1. Em linfomas de clulas do manto em estdio avanado, sem tratamento prvio, a adio de rituximab ao esquema CHOP aumentou as taxas de resposta (completa e parcial) com aumento do tempo para falncia do tratamento, porm sem benefcio em sobrevida livre de doena. (J Clin Oncol. 2005 Mar 20;23(9):1984-92) 2. Em anlise de subgrupo com apenas 40 pacientes (Blood. 2004 Nov 15;104(10):3064-71), a adio de Rituximab ao esquema FCM para tratamento de linfoma do manto em recada aumentou significativamente a taxa de resposta e a sobrevida total. 3. No linfoma folicular grau III ou IV, sem tratamento prvio, a adio de rituximab ao esquema CVP aumenta significativamente as taxas de resposta parcial e completa inicial e os tempos para progresso e falncia do tratamento(Blood. 2005 Feb 15;105(4):1417-23.). No h anlise de sobrevida. 4. Em anlise de subgrupo com 93 pacientes (Blood. 2004;104(10):3064-71.) a adio de Rituximab ao esquema FCM para tratamento de linfoma folicular III ou IV em recada aumentou significativamente a taxa de resposta e a sobrevida total 5. O uso de rituximab(4 doses bimestrais) para manuteno de linfomas foliculares, recm diagnosticados ou em recada e responsivos a um esquema inicial de rituximab, aumentou a sobrevida livre de doena em aproximadamente 1 ano(Blood. 2004 Jun 15;103(12):4416-23) C. Benefcio no-definido 1. Para leucemia linfoctica crnica no existem dados suficientes para sua indicao teraputica. 2. O uso de rituximab para manuteno de linfomas do manto, recm diagnosticados ou em recada, no mostrou benefcios nas taxas e durao da resposta.( Clin Oncol. 2005 Feb 1;23(4):705-11)

REFERNCIAS BIBLIOGRFICAS

1. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. 2. Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, Sebban C, Berger F, Bosly A, Morel P, Tilly H, Bouabdallah R, Reyes F, Gaulard P, Coiffier B. Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003 Jun 1;101(11):4279-84 3. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med. 2002 Jan 24;346(4):235-42.. 4. Hornberger JC, Best JH. Cost utility in the United States of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone for the treatment of elderly patients with diffuse large B-cell lymphoma. Cancer. 2005 Apr 15;103(8):1644-51. 5. Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005 Mar 20;23(9):1984-92. 6. Ghielmini M, Schmitz SF, Cogliatti S, Bertoni F, Waltzer U, Fey MF, Betticher DC, Schefer H, Pichert G, Stahel R, Ketterer N, Bargetzi M, Cerny T; Swiss Group for Clinical Cancer Research. Effect of singleagent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005 Feb 1;23(4):705-11.

7. Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71 8. Forstpointner R, Hanel A, Repp R, Hermann S, Metzner B, Pott C, Hartmann F, Rothmann F, Bock HP, Wandt H, Unterhalt M, Hiddemann W. Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group] Dtsch Med Wochenschr. 2002 Oct 25;127(43):2253-8. 9. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P . CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. 10. Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. 11. Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani MFludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61 12. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny TProlonged treatment with rituximab in patients

with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. 13. Forstpointner R, Hanel A, Repp R, Hermann S, Metzner B, Pott C, Hartmann F, Rothmann F, Bock HP, Wandt H, Unterhalt M, Hiddemann W. Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group] Dtsch Med Wochenschr. 2002 Oct 25;127(43):2253-8. 14. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin's lymphoma: a systematic review and economic evaluation. Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, Davenport C. Health Technology Assessment 2002; 6(3): 1-85. 15. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14 16. Khouri IF, Saliba RM, Hosing C, Okoroji GJ, Acholonu S, Anderlini P, Couriel D, De Lima M, Donato ML, Fayad L, Giralt S, Jones R, Korbling M, Maadani F, Manning JT, Pro B, Shpall E, Younes A, McLaughlin P, Champlin RE. Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2005 Apr 1;23(10):2240-7. 17. Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005 Sep 1;106(5):1538-43.

Contatos com: Unimed Santa Catarina Assessoria de Projetos Especiais Fax: (0XX) 47 3441-0516 E-mail: cardim.joi@terra.com.br akoenig@unimedsc.com.br