Linfomas Foliculares

Transcrição

1 Linfomas Foliculares VI Board Review Hematologia Centro de Oncologia e Hematologia Hospital Israelita Albert Einstein Dr Jacques Tabacof

2 Linfomas Não-Hodgkin Células B BL (0.8%) High-grade B, NOS Splenic MZ (0.9%) (2.5%) Nodal MZ (2%) PMBL (3%) Lymphoplasmacytic (1.4%) CLL/SLL (12%) MCL (7%) DLBCL (37%) MALT (9%) FL (29%) BL = Burkitt s lymphoma MALT = mucosal associated lymphoid tissue MZ = marginal zone SLL = small lymphocytic leukaemia NOS = not otherwise specified PMBL = primary mediastinal B cell lymphoma Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4 th edition). Lyon, France: IARC Press, 2008.

3 Linfomas: Originam-se de Linfócitos em diferentes estágios de diferenciação Somatic Hypermutation Nogai H et al. JCO 2011;29:

4 t(14;18) evento iniciador na patogênese molecular dos Linfomas Foliculares Nogai H et al. JCO 2011;29:

5 Linfomas Foliculares 30 % dos LNH Incidência 4: Idade mediana 60 anos Sintomas B raros Graus I II IIIa e IIIb Citogenética: t(14;18) 85 % BCL-2 proximo a gene IgH Hiperexpressão bcl-2 Interfere na apoptose Bcl-2 CD10

6 Linfoma Foliculares Diagnosticado em estadios avançados Sensíveis a Quimioterapia e Radioterapia Recidivas são frequentes Respostas cada vez mais curtas Causas de óbito Transformação Refratariedade Infecções

7 Follicular Lymphoma International Prognostic Index (FLIPI) Nodal regions > 4 Elevated LDH Age > 60 Stage III/IV Solal-Celigny P, et al. Blood 2004; 104: Haemoglobin < 12 g/dl Risk group Factors (n) Probability of survival Good Months Patients (%) 5-year OS 10-year OS Low % 70.7% Intermediate % 50.9% High % 35.5% 0.2 Intermediate Poor p <

8 Mannikin used for counting the number of involved areas Solal-Celigny, P. et al. Blood 2004;104:

9 FLIPI 2 Factors Independently Predictive for PFS β2-microglobulin higher than the upper limit of normal Longest diameter of the largest involved node longer than 6 cm Bone marrow involvement Hemoglobin level lower than 12 g/dl Age older than 60 years Federico M et al. JCO 2009;27:

10 (A) Progression-free survival (PFS) and (B) overall survival (OS) of the training sample (832 patients) according to the Follicular Lymphoma International Prognostic Index 2 (FLIPI2); (C) PFS and (D) OS of the validation sample (231 patients) according to FLIPI2. Federico M et al. JCO 2009;27:

11 Linfoma Não-Hodgkin Baixo Grau Estadios Iniciais % doença localizada (estadios I e II) Tratamento Standard: Radioterapia Campo Envolvido % sem recidiva em 10 anos 30 Gy controle 90 % no campo irradiado Recidiva Sistêmica

12 Radioterapia Campo Envolvido Centro N SLD 10 a SG 10 a BNLI % 52 % BNLI % 64 % (est I) PMH % 58 % (12 a) Stanford % 64 % MDACC % 43 % (15 a) Royal M % 79 %

13 Tentativas de Otimização Estadiamento com Laparotomia Campos de Irradiação Extensos Extended-Field Irradiação Linfóide Total Tratamento Sistêmico

14 Linfoma Não-Hodgkin Baixo Grau Estadios Iniciais Conclusões Situação Rara Tratamento standard Radioterapia Campo Envolvido Dose Gy Curabilidade 50 % 10 anos Tratamentos sistêmicos utilizados em alguns centros Pacientes selecionados podem ser poupados do tratamento

15 Opções de Tratamento Estadios Avançados Observação cuidadosa watch and Wait Agentes alquilantes Fludarabina Rituximabe CVP; CHOP FND; FCM R CVP; R CHOP; R FND Radioimunoconjugados TAMO, TMO alogênico RT Vacinas e alfa interferon Manutenção

16 Watchfull Waiting (acompanhamento sem tratamento) Horning et al NEJM 1984 História natural sem tratamento N = 83 Sobrevida 5 anos 82 % Sobrevida 5 anos 82 % Sobrevida 10 anos 73 % Tempo médio para terapia 3 anos Regressão espontânea 23 % Frequência e tempo para transformação semelhante a controle histórico tratado

17 Watch & wait versus immediate treatment for asymptomatic advanced stage indolent NHL Overall survival Cumulative survival (%) Years Observation (n = 151) Chlorambucil (n = 153) Median 5-year 10-year 15-year Chlorambucil 5.9 years 57% 35% 21% Observation 6.7 years 58% 34% 22% Ardeshna KM, et al. Lancet 2003; 362:

18 An Intergroup Randomised Trial of Rituximab Versus a Watch and Wait Strategy in Patients with Stage II, III, IV, Asymptomatic, Non-bulky Follicular Lymphoma (Grades 1, 2 and 3a) A Preliminary Analysis KM Ardeshna et al. ASH 2010; Abstract 6, oral Blood, Volume 116, Issue 21

19 Watch and wait: Study design Primary endpoints: Time to initiation of new therapy (chemotherapy or radiotherapy) Effect on quality of life Asymptomatic stage 2, 3 or 4 FL Grades 1, 2 & 3a Adequate bone marrow reserve Progressive disease requiring therapy stops protocol treatment R A N D O M I S E ARM A Watchful waiting ARM B R-mono 375 mg/m 2 weekly x 4 ARM C R-mono 375 mg/m 2 weekly x 4 + maintenance q2mo for 2 years DISCONTINUED ARM A Watchful waiting ARM B X R-mono 375 mg/m 2 weekly x 4 ARM C R-mono 375 mg/m 2 weekly x 4 + maintenance q2mo for 2 years Total planned enrolment: 360 patients Ardeshna KM, et al. Blood 2010;116:Abstract 6.

20 Time to initiation of new therapy (TTINT) Proportion of patients with no new treatment initiated W+W R4 R4 + M Events Totals % not requiring Rx at 3 yrs W+W = 48% R4 = 80% R4+RM = 91% Years from randomisation HR (R-mono vs W+W) = 0.37; 95%CI = 0.25, 0.56; p < HR (R-mono + maintenance vs W+W) = 0.20; 95% CI = 0.13, 0.29; p < HR (R-mono + maintenance vs R-mono) = 0.57; 95% CI = 0.29, 1.12; p = 0.10 Ardeshna KM, et al. Blood 2010;116:Abstract 6.

21 Overall Survival yr OS = 95% % of patients alive W+W R4 R4 + M Events Totals Years from randomisation HR (R-mono vs W+W) = 0.63; 95%CI = 0.21, 1.92; p = 0.42 HR (R-mono + maintenance vs W+W) = 0.84; 95%CI = 0.32, 2.18; p = 0.72 HR (R-mono + maintenance vs R-mono) = 1.21; 95%CI = 0.37, 3.97; p = 0.75 Ardeshna KM, et al. Blood 2010;116:Abstract 6.

22 Watch and Wait Motivos a favor Observar ritmo da doença Não piora sobrevida (tratamentos antigos) Tempo para tratamento 2 anos 20 % falecem sem necessitar tratamento Estudos atuais R-QT: elegiveis só sintomáticos, massa > 7 cm, alt laboratoriais

23 Watch and Wait Motivos Contra Observar não aumenta sobrevida Tratamentos atuais parecem impactar sobrevida Tratar pessoas que não precisam é prática comum em oncologia Dogma oncológico: menor volume maior chance de cura Rituximabe aumento o tempo para tratamento (QT)

24 LNH baixo grau Stanford Sobrevida 100 Percentage survival Time (years) Horning SJ. Semin Oncol 1993;20(5 Suppl. 5):75 88

25 Clorambucil + Prednisona vs. CHOP LNH indolente sintomático 259 pacientes estadios avançados, não tratados, sintomáticos ORR: Ch/P 36% versus CHOP 60% (p< 0.01) Sobrevida 5 anos = 41% versus 44% (p=ns) Sobrevida mediana = 46 versus 52 m (p=ns) Kimby E, et al. Ann Oncol 1994;5(Suppl.2):67 71

26 Doxorubicina e LNH de Baixo Grau JCO/1993 Dana BW, Fisher RI, et al SWOG 7204, 7426 e 7713 N = 415 estadios III e IV FU mediano 12,8 anos Sobrevida mediana 6,9 anos Conclusão: Doxorubicina não aumenta sobrevida em comparação com programas menos intensos

27 CALGB Linfoma Folicular Monoterapia vs Poliquimioterapia 1.0 DFS 1.0 OS Cyclophosphamide Cyclophosphamide Proportion disease-free CHOP + bleomycin Proportion surviving CHOP + bleomycin Years from entry Years from entry Peterson BA, et al. J Clin Oncol 2003;21:5 15

28 Rituximab: Anticorpo Quimérico Humano/Murino Regão variável murina liga CD 20 Região Constante kappa Humana Dominio Fc Humano IgG 1 sinergia com mecanismos efetores humanos IgG1 Quimérico Rybak et al. Proc Natl Acad Sci USA. 1992;89:3165.

29 Reference Referência MabThera agente único Linfoma Folicular Pacientes Previamente tratados n OR (%) CR (%) Duração da resposta Maloney DG, Duration of response (months) (meses) McLaughlin P, Davis TA, Foran JM, Hainsworth JD, Colombat P, SAKK Overall Geral RG RC

30 Monoterapia com Rituximab Primeira Linha 100 Taxa de resposta (%) após a primeira avaliação Global Parcial Completa Estável Melhora depois da primeira avaliação: 7/23 respondedores parciais tinham respostas completas 3/10 pacientes com doença estável tinham respostas parciais Colombat P, et al. Blood 97: , 2001

31 Mabthera + Quimioterapia vs Quimioterapia Pacientes Sintomáticos Quatro Estudos Randomizados Aumento da SLD e da Sobrevida Global R-CVP vs CVP (Marcus) R-CHOP vs CHOP (Hiddeman) R-MCP vs MCP (Herold) R-CHVP/INF vs CHVP/INF (Salles)

32 Overall survival CVP or R-CVP Marcus, R. et al. J Clin Oncol; 26:

33 OS after start of therapy for CHOP and R-CHOP p = 0,016 P 0 Hiddemann, W. et al. Blood 2005;106:

34 Overall survival MCP or R-MCP Herold, M. et al. J Clin Oncol; 25:

35 FL2000 study with a 5-year median follow-up Salles, G. et al. Blood 2008;112:

36 Indução com Quimioterapia e Rituximab Aumenta Sobrevida Induction regimen Outcome (median) CHVP ± R + IFN-α 1 EFS NR vs 3 yrs p < Overall survival 3.5 yr 91% vs 84% p = MCP ± R 2 PFS NR vs 29 mo 4 yr 87% vs 74% p < p = CHOP ± R 3 TTF NR vs 31 mo p = CVP ± R 4 TTP 34 mo vs 15 mo p < yr 95% vs 90% p = yr 83% vs 77% p = Foussard C, et al. J Clin Oncol 2006; 24:Abstract Herold M, et al. J Clin Oncol 2007; April 9 (Epub). 3. Hiddemann W, et al. Blood 2005; 106: Marcus R, et al. Blood 2006; 108:Abstract 481.

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38 R-CVP vs R-CHOP vs R-FM para Linfoma Folicular Avançado Sem Tratamento Prévio Ref.: Federico M et al. J Clin Oncol 30, 2012

39 R-CVP vs R-CHOP vs R-FM para Linfoma Folicular Avançado Sem Tratamento Prévio Ref.: Federico M et al. J Clin Oncol 30, 2012

40 R-CVP vs R-CHOP vs R-FM para Linfoma Folicular Avançado Sem Tratamento Prévio Ref.: Federico M et al. J Clin Oncol 30, 2012

41 BENDAMUSTINE Bendamustine was synthesized as a unique chemical structure combining an alkylating group with a purine-like benzimidazole ring in 1963 The alkylating group contains mechlorethamine, which confers alkylating properties The benzimidazole component contains a purinelike benzimidazole ring

42 Bendamustine B-R vs CHOP-R 549 pacientes sintomáticos (FL 55% MCL 18% e Indolentes 27%) Estadio IV 78 % B-R CHOP-R 6 ciclos 82% 86% RR 93,8% 93,5% CR 40,1% 30,8% p 0,032 PFS 54,8 m 34,8 m HR 0,57 Rummel MJ et al ASH 2009 abst 405

43 Bendamustine B-R vs CHOP-R Toxicidade B-R CHOP-R Neutropenia G3-4 (%) 10,7 46,5 Alopecia (%) 15 G1 62 Infecção Neuropatia Periférica Rash Rummel MJ et al ASH 2009 abst 405

44 PFS by subentities for R-bendamustine vs R-CHOP Follicular 0.8 B-R 0.7 p = 0, Follicular p = 0, Marginal zone Marginal zone B-R CHOP-R CHOP-R p = p = B-R 0.6 B-R 0.5 CHOP-R CHOP-R 1.0 Mantle cell Mantle p = 0,0146 cell p = 0, B-R CHOP-R B-R CHOP-R Waldenström Waldenström p = B-R 0.6 B-R p = CHOP-R CHOP-R (ASH 2009, Abstract 405, Rummel et al)

45 Bendamustina-Rituximabe vs CHOP- Rituximabe em Linfomas Indolentes Ref.: Rummel MJ et al. J Clin Oncol 30, 2012 (suppl; abstr 3)

46 Lenalidomide + Rituximab Rituximab d1 Lenalidomide d1-21 qd 4 wks 75 pts with indolent NHL (FL, MZL, CLL) Previously untreated RR 90% CR 66% (87% in FL) 52 pts with relapsed/resistant MCL RR 58% CR 33% Fowler et al., Abstr. 137, ICML-11 Wang et al., Abstr. 109, ICML-11

47 LNH baixo grau Stanford Sobrevida 100 Percentage survival Time (years) Horning SJ. Semin Oncol 1993;20(5 Suppl. 5):75 88

48 Fisher RI, et al. J Clin Oncol 2005; 23: Fisher, R. I. et al. J Clin Oncol; 23:

49 Overall survival improvement with rituximab in FL 1.0 GLSG study NHL 2000 Survival probability GLSG study NHL 1996 p < Number of patients at risk: NHL 1996 NHL 2000 Time (months) Hiddemann W, et al. Blood 2006; 108:Abstract 483.

50 Overall survival according to treatment regimen Liu, Q. et al. J Clin Oncol; 24:

51 Conclusões Mabthera + Quimioterapia Indução R-QT resultados superiores em estudos prospectivos randomizados e meta-análise Aumento da Sobrevida Livre de Progressão e da Sobrevida Global Melhor regime de indução? R-CHOP, R-B, R-CVP,R-FCM

52 Linfomas de Baixo Grau Manutenção

53 Objetivos da terapia de Manutenção Manter remissão/atrasar recidiva Melhorar a qualidade da resposta (PR CR) Controlar doença residual mínima Adiar ou diminuir necessidade de quimioterapias subsequentes Manter QoL com mínima toxicidade Administração simples e cômoda Ausência de toxicidade aguda/cumulativa Prolongar sobrevida

54 Linfoma Baixo Grau Manutenção Alfa-Interferon FDA approved for maintenance Meta analysis + (combined with chemo) Relevant toxicity Impact after R-Chemo? Hiddemann, Herold, Salles studies INF maintenance Marcus study no INF Not usually used in clinical practice in Brazil

55 SAKK 35/98 study design n=202 n=151 Observation MabThera 375mg/m² weekly x 4 PD off study R SD, PR, CR MabThera 375mg/m² every 2 months x 4 Prolonged treatment Ghielmini M, et al. Blood 2004;103:

56 SAKK35/98: event-free survival in previously untreated or relapsed indolent NHL 1.0 Probability Prolonged treatment (n=73): median 23.2 months p=0.024 Observation (n=78): median 11.8 months Months since start of treatment Ghielmini M, et al. Blood 2004;103:

57 SAKK 35/98 Sobrevida Livre de Eventos Abstract 8512 ASCO 2009

58 CVP ± maintenance MabThera (ECOG 1496): study treatment CVP R E S T A G E CR, PR, SD R A N D O M IS E Stratify: histology, residual disease Maintenance rituximab (MR) Observation (Obs) C = cyclophosphamide 1,000mg/m 2 i.v. day 1 V = vincristine 1.4mg/m 2 (maximum = 2) i.v. day 1 P = prednisone 100mg/m 2 p.o. days 1 5 Repeat every 21 days; best response + two cycles (6 8) MR = MabThera 375mg/m 2 weekly x 4 Start 4 weeks after CVP; every 6 months for 2 years Hochster HS, et al. Proc Am Soc Clin Oncol 2004;23:556 (Abstract 6502)

59 (A) Progression-free survival (PFS) for 311 evaluable indolent lymphoma patients randomly assigned to maintenance rituximab (MR; n = 158) or observation (OBS; n = 153) (B) PFS for 228 evaluable follicular lymphoma patients randomly assigned to MR (n = 115) or OBS (n = 113). Hochster, H. et al. J Clin Oncol; 27:

60 A. OS 311 evaluable indolent lymphoma patients randomly assigned to maintenance rituximab (MR; n = 158) or observation (OBS; n = 153) B. OS for 288 evaluable follicular lymphoma patients randomly assigned to MR (n = 115) or OBS (n = 113). Hochster, H. et al. J Clin Oncol; 27:

61 EORTC phase III trial: Resistant/Relapsed R A N D O M I S A T I O N CHOP every 21 days (maximum six cycles) MabThera + CHOP every 21 days (maximum six cycles) CR PR R A N D O M I S A T I O N Observation MabThera maintenance* *375mg/m 2 every 3 months for 2 years or until relapse

62 Progression-free survival (%) Intergroup phase III trial: PFS from second randomization all patients Overall log-rank test: p< Hazard ratio: 0.40 MabThera maintenance median: 51.6 months Observation median: 15.0 months Years O N Number of patients at risk Treatment Observation MabThera

63 Intergroup phase III trial: PFS from second randomization by induction regimen Subgroups according to induction treatment Progression-free survival (%) Progression-free survival after CHOP Overall log-rank test: p<0.0001; HR: Years Median 42.0 months Median 11.6 months O N Number of patients at risk : Treatment Observation MabThera Progression-free survival (%) Progression-free survival after R-CHOP Median 51.9 months Median 23.1 months Overall log-rank test: p=0.004; HR: Years O N Number of patients at risk : Treatment Observation MabThera

64 Overall survival (%) Intergroup phase III trial: overall survival from second randomization Overall log-rank test: p=0.011 HR: 0.52 MabThera maintenance 3 yrs 85.1% Observation 3 yrs 77.1% Years O N Number of patients at risk : Treatment Observation MabThera

65 EORTC years follow up EFS Rituximab maintenance 3.7 years Observation arm 1.3 years p<0.0001; hazard ratio 0.55 OS 5 years Rituximab maintenance 74 % Observation arm 64 % p = 0.07

66 FCM versus R-FCM: relapsed indolent lymphoma OS was significantly increased in the R-FCM induction arm compared to FCM alone (p=0.031) all subsequent patients received R-FCM induction Fludarabine Cyclophosphamide Mitoxantrone PR, CR R Fludarabine Cyclophosphamide Mitoxantrone + rituximab Watch and wait 4 x rituximab (month 3) 4 x rituximab (month 9)

67 Advantage for rituximab maintenance over observation in response duration and overall survival Response duration R-maintenance vs observation after FCM p-value p= R-maintenance vs observation after R-FCM R-maintenance vs observation after R-FCM FL MCL p= p= p= Overall survival R-maintenance vs observation after R-FCM p-value p=0.0562

68 R manutenção Linfoma. Folicular R-FCM indução Response Duration Forstpointner R et al. Blood 2006;108:

69 Studies of rituximab maintenance therapy in follicular NHL Study/group Trial design Setting Study induction Rituximab maintenance Minnie Pearl 1* Ph. II 1 st line Rituximab OR 74%,PFS 37mo SAKK 35/98 2 Ph. III 1 st /2 nd line Rituximab EFS mo Minnie Pearl 3* Ph. II 2 nd line Rituximab PFS 7 31 mo ECOG Ph. III 1 st line CVP PFS mo EORTC Ph. III 2 nd line CHOP ± R PFS mo GLSG 6 Ph. III 2 nd line FCM ± R RD 19 NR (3y) * Included patients with small lymphocytic lymphoma Randomized maintenance versus retreatment Included patients with MCL 1. Hainsworth JD, et al. J Clin Oncol 2002; 20: Ghielmini M, et al. Blood 2004; 103: Hainsworth JD, et al. J Clin Oncol 2005; 23: Hochster HS, et al. Proc Am Soc Clin Oncol 2004; 22:Abstract van Oers M, et al. Blood 2004; 104:Abstract Hiddemann W, et al. Proc Am Soc Clin Oncol 2005; 23:Abstract 6527.

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71 Manutenção R-QT superior a QT de indução R manutenção eficaz após QT e após R-CHOP, R-FCM em segunda linha Papel da Manutenção em pacientes tratados com R-QT em primeira linha???

72 PRIMA: study design INDUCTION MAINTENANCE Registration High tumor burden untreated follicular lymphoma Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM CR/CRu PR Rituximab maintenance 375 mg/m 2 every 8 weeks for 2 years Random 1:1* PD/SD off study Observation * Stratified by response after induction, regimen of chemo, and geographic region Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up

73 Patient disposition Induction Maintenance Patients evaluable (N = 1202)* R-CHOP N = 885 Randomized N = 769 Patients registered: N = 1217 R-CVP N = 272 Randomized N = 222 Patients randomized: N = 1018 R-FCM N = 45 Randomized N = 28 * 15 pts in 3 sites closed prematurely 9 pts did not receive chemo 147 pts withdrew during or at the end of induction (failure to respond; toxicity) 28 pts failed to be randomized 1 pt died during the randomization process Observation N = 513 Rituximab N = 505

74 Primary endpoint (PFS) met at the planned interim analysis Rituximab maintenance significantly reduced the risk of progression by 50% Progression-free rate Patients at risk stratified HR= % CI 0.39; 0.64 p<.0001 Time (months) 82% % Rituximab maintenance N=505 Observation N=513

75 Safety during rituximab maintenance 100 Patients (%) Observation (n = 508) Rituximab maintenance (n = 501) Any adverse event Grade 2 infections 23 <1 16 <1 4 <1 4 Grade 3/4 adverse events Grade 3/4 neutropenia Grade 3/4 infections

76 Benefits of rituximab maintenance seen in sub-groups evaluated Category Subgroup Hazard ratio N Hazard ratio* 95% CIs All All Age < FLIPl Index FLIPl 1 FLIPl = 2 FLIPl Induction R-CHOP Chemotherapy R-CVP R-FCM Response to Induction CR/CRu PR Favors maintenance Favors observation * Non-stratified analysis

77 PRIMA impacto do regime de indução R-CHOP R-CVP R-FCM RR 92,8 84,7 75 CR/Cru 67, ,4 SAE Neutropenia febril Lugano 2011 abst 022

78 PRIMA : Impacto do regime de indução 3 ANOS (%) R-CHOP R-CVP R-FCM PFS Manutenção PFS Observação OS Manutenção OS Observação 78,6 61,6 78,6 59, ,3 95,6 93,7 74,5 95,2 89,9 100 R-CHOP Melhor Taxa de Resposta e PFS Efeito mais substancial da manutenção

79 LNH The Maintain Study N=591 Observação B-R + R m 2 anos Rituximabe Manutenção 2 anos

80 RECIDIVAS

81 Sobrevida global LNH baixo grau TMO alogênico condicionamento clássico 1.00 Percent survival N = Years EBMT registry

82 CUP Trial Sobrevida Global Transplante Autólogo

83 Remission duration of all patients HD SCT St Bart s TBI Rohatiner, A. Z.S. et al. J Clin Oncol; 25:

84 EBMTR Linfoma Folicular Transplante Autólogo PFS Montoto et al Leukemia 2007

85 EBMTR Linfoma Folicular Transplante Autólogo OS Montoto et al Leukemia 2007

86 EBMTR Linfoma Folicular Transplante Autólogo Montoto et al Leukemia 2007

87 Conclusões I Radioterapia é o tratamento recomendado para estadios I e II Acompanhamento sem tratamento (W/W) é uma opção, Rituximabe em assintomáticos pode adiar QT/RT R-QT de indução seguido de R manutenção por 2 anos é o tratamento considerado padrão ouro em pacientes sintomáticos Está havendo ganhos em sobrevida global

88 Conclusões II Transplante Alogênico de MO é potencialmente curativo Quimioterapia em Altas Doses (TAMO) tem papel em casos selecionados Recidiva quimiossensível Evitar TBI

89 Linfoma de Células do Manto 6-7 % dos Linfomas B, Idade mediana 60 anos t(11;14) Expressão de ciclina D1 Não expressa em Linfócitos normais Regula ciclo celular transição G1-S Envolvimento MO, SP, TGI, Anel de Waldeyer Agressivo, recidivante, sobrevida mediana 3 a Clássico 80 %, Indolente 15%, Blastóide 5 %

90 Linfoma do Manto Atenção ao envolvimento TGI

91 Tipos Histológicos MCL Typical MCL Pleomorphic Variant Blastoid Variant Cyclin D1 + nuclei

92 Linfoma do Manto: defeito no controle do ciclo celular e da resposta ao dano do DNA Nogai H et al. JCO 2011;29:

93 Linfoma do Manto CCND1 negativo Existe! Expressão Gênica semelhante a CCND1 + Alta expressão e translocações de CCND2 e CCND3 CCND2 e D3 expressas em outros LNH SOX11 pode auxiliar no diagnóstico

94 Linfoma do Manto Indolente Existe! Fatores Prognósticos Favoráveis Ki67 baixo Estadio Limitado Apresentação não-nodal, esplenomegalia, fase leucêmica SOX11 negativo

95 Overall survival according to the combined biologic index (MIPIb) in 220 patients with Ki-67 available times age (years) (if ECOG > 1) times log10(ldh/uln) times log10(wbc count) times Ki-67 (%). EMCL network calculator Hoster E et al. Blood 2008;111:

96 MCL treatment modalities Single agent chemotherapy Polychemotherapy regimens (+/- doxorubicin) Purine analogues based Intensive regimens (with HD-AraC) Monoclonal antibodies Auto and Allo BMT Experimental treatments

97 Combination chemotherapy MCL (series with n = 26-62) Regimen RR (%) EFS (mos) 2yOS (%) CVP CHOP MCP R-CHOP R-MCP Ghielmini and Zucca, Blood 2009

98 Linfoma do. Manto TTF GLSG Lenz G et al. JCO 2005;23:

99 . R manutenção Pós R-FCM Linfoma do Manto Response Duration Forstpointner R et al. Blood 2006;108:

100 PFS by subentities for R-bendamustine vs R-CHOP Follicular 0.8 B-R 0.7 p = 0, Follicular p = 0, Marginal zone Marginal zone B-R CHOP-R CHOP-R p = p = B-R 0.6 B-R 0.5 CHOP-R CHOP-R 1.0 Mantle cell Mantle p = 0,0146 cell p = 0, B-R CHOP-R B-R CHOP-R Waldenström Waldenström p = B-R 0.6 B-R p = CHOP-R CHOP-R (ASH 2009, Abstract 405, Rummel et al)

101 R-CHOP vs R-FC + R manutenção Idosos! > 60 anos MCL Network n = 559 > 60 anos Duas Randomizações 8 R-CHOP21 vs 6 R-FC28 Rituximab vs alfa-interferon Lugano 2011 abst 016

102 R-CHOP vs R-FC + R manutenção Idosos! R-CHOP R-FC p RR % ,0581 CR % OS m ,0117

103 R-CHOP vs R-FC + R manutenção Manutenção Idosos! Duração da Remissão Rituximabe 51 m Alfa Interferon 24 m p 0,012 R-CHOP21 R man. SG 3 a 83 % Novo standard! Lugano 2011 abst 016

104 Intensification with Ara-C (series with n = 25 97) RR (%) CR (%) Hyper CVAD/MTX-AraC R-Hyper CVAD/MTX-AraC CHOP / DHAP R-CHOP / R-DHAP Toxic deaths: 0-8% Severe infections: 5-30% Severe thrombocytopenia: 30-80% Ghielmini and Zucca, Blood 2009

105 The role of high-dose cytarabine in MCL p= (one sided sequential test) Hermine et al., ASH 2010

106 The Nordic trial of PBSCT in MCL n = 160 Age < 66 MCL 2 R-maxi CHOP R-HD-AraC R-in-vivo purging BEAM MCL 1 maxi CHOP BEAM Geisler et al., Blood 2008

107 Nordic Lymphoma Group MCL2 trial acompanhamento 10 anos N = 160 CHOP/Ara-C TAMO com BEAM SG 10 anos 57 % EFS 10 anos 42 % MIPI válido MIPI alto risco apresenta recidivas tardias Lugano 2011 abst 102

108 R-CHOP/R-DHAP TAMO Jovens! < 65 anos MCL net n = 497 randomizado R-CHOP21 X 6 TAMO TBI 12 Gy R-CHOP/R-DHAP X 6 TAMO TBI 10 Gy Lugano 2011 abst 023

109 R-CHOP/R-DHAP TAMO Jovens! R-CHOP R-DHAP RR % p 0,19 CR/Cru % p 0,012 TAMO % CR TAMO % TTTF m 49 NR p 0,0384 HR 0,68 OS 3 anos 79 80

110 Novas Drogas Bortezomib Lenalidomide Temsirolimus Everolimus N RR CR EFS % 8% 6m 15 53% 20% 6m 54 22% 2% 5m 35 20% 6% 5m Fisher et al., JCO 2006 Habermann et al, BJH 2009 Hess et al, JCO 2009 Renner et al, ASH 2010

111 . Bortezomib Fase II Linfoma do Manto Refratário e Recidivado N 141 Fisher R I et al. JCO 2006;24:

112 Estadios I e II Linfoma do Manto BCCA 26 pacientes Leitch Ann Oncol 2003

113 Linfoma do Manto > 60 anos R-CHOP X 6 R manut R-CVP R-B < 60 anos R-CHOP/R-DHAP BEAM R-HyperCVAD/R-MTX-Ara-C BEAM Recidivas ICE mini alo (jovens) Bortezomibe Lenalidomida Bendamustine

114 OBRIGADO