Linfomas Foliculares

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

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.

Linfomas: Originam-se de Linfócitos em diferentes estágios de diferenciação Somatic Hypermutation Nogai H et al. JCO 2011;29:1803-1811

t(14;18) evento iniciador na patogênese molecular dos Linfomas Foliculares Nogai H et al. JCO 2011;29:1803-1811

Linfomas Foliculares 30 % dos LNH Incidência 4:100000 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

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

Follicular Lymphoma International Prognostic Index (FLIPI) Nodal regions > 4 Elevated LDH Age > 60 Stage III/IV Solal-Celigny P, et al. Blood 2004; 104:1258 1265 Haemoglobin < 12 g/dl Risk group Factors (n) Probability of survival 1.0 0.8 0.6 0.4 Good 0 0 12 24 36 48 60 72 84 Months Patients (%) 5-year OS 10-year OS Low 0 1 36 90.6% 70.7% Intermediate 2 37 77.8% 50.9% High 3 5 27 52.5% 35.5% 0.2 Intermediate Poor p < 0.0001

Mannikin used for counting the number of involved areas Solal-Celigny, P. et al. Blood 2004;104:1258-1265

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;27:4555-4562

(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;27:4555-4562

Linfoma Não-Hodgkin Baixo Grau Estadios Iniciais 10-20 % doença localizada (estadios I e II) Tratamento Standard: Radioterapia Campo Envolvido 30-50 % sem recidiva em 10 anos 30 Gy controle 90 % no campo irradiado Recidiva Sistêmica

Radioterapia Campo Envolvido Centro N SLD 10 a SG 10 a BNLI 82 28 % 52 % BNLI 208 47 % 64 % (est I) PMH 190 53 % 58 % (12 a) Stanford 177 44 % 64 % MDACC 80 41 % 43 % (15 a) Royal M 58 43 % 79 %

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

Linfoma Não-Hodgkin Baixo Grau Estadios Iniciais Conclusões Situação Rara Tratamento standard Radioterapia Campo Envolvido Dose 30-40 Gy Curabilidade 50 % 10 anos Tratamentos sistêmicos utilizados em alguns centros Pacientes selecionados podem ser poupados do tratamento

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

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

Watch & wait versus immediate treatment for asymptomatic advanced stage indolent NHL Overall survival Cumulative survival (%) 100 80 60 40 20 0 0 Years Observation (n = 151) Chlorambucil (n = 153) 4 8 12 16 20 24 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; 362:516 522

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

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.

Time to initiation of new therapy (TTINT) 1.0 0.9 Proportion of patients with no new treatment initiated 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 W+W R4 R4 + M Events Totals 83 187 19 84 19 192 % not requiring Rx at 3 yrs W+W = 48% R4 = 80% R4+RM = 91% 1 2 3 4 5 Years from randomisation HR (R-mono vs W+W) = 0.37; 95%CI = 0.25, 0.56; p < 0.001 HR (R-mono + maintenance vs W+W) = 0.20; 95% CI = 0.13, 0.29; p < 0.001 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.

Overall Survival 1.0 0.9 0.8 3yr OS = 95% % of patients alive 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 W+W R4 R4 + M Events Totals 9 187 4 84 8 192 1 2 3 4 5 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.

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

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)

LNH baixo grau Stanford Sobrevida 100 Percentage survival 80 60 40 20 1987 1992 1976 1986 1960 1975 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (years) Horning SJ. Semin Oncol 1993;20(5 Suppl. 5):75 88

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

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

CALGB Linfoma Folicular Monoterapia vs Poliquimioterapia 1.0 DFS 1.0 OS Cyclophosphamide Cyclophosphamide Proportion disease-free 0.8 0.6 0.4 0.2 CHOP + bleomycin Proportion surviving 0.8 0.6 0.4 0.2 CHOP + bleomycin 0 0 2 4 6 8 10 12 14 16 18 0 0 2 4 6 8 10 12 14 16 18 Years from entry Years from entry Peterson BA, et al. J Clin Oncol 2003;21:5 15

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.

Reference Referência MabThera agente único Linfoma Folicular Pacientes Previamente tratados n OR (%) CR (%) Duração da resposta Maloney DG, 1997 34 50 9 10.2 Duration of response (months) (meses) McLaughlin P, 1998 118 60 6 13.0 Davis TA, 1999 22 55 8.0 Foran JM, 2000 70 46 3 11.0 Hainsworth JD, 2000 25 52 5 Colombat P, 2000 50 73 20 SAKK 2001 183 54 8 12 Overall Geral 50 60 5 10 12 RG RC

Monoterapia com Rituximab Primeira Linha 100 Taxa de 80 73 resposta (%) após a primeira avaliação 60 40 20 47 26 20 0 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 97:101-106, 2001

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)

Overall survival CVP or R-CVP Marcus, R. et al. J Clin Oncol; 26:4579-4586 2008

OS after start of therapy for CHOP and R-CHOP p = 0,016 P 0 Hiddemann, W. et al. Blood 2005;106:3725-3732

Overall survival MCP or R-MCP Herold, M. et al. J Clin Oncol; 25:1986-1992 2007

FL2000 study with a 5-year median follow-up Salles, G. et al. Blood 2008;112:4824-4831

Indução com Quimioterapia e Rituximab Aumenta Sobrevida Induction regimen Outcome (median) CHVP ± R + IFN-α 1 EFS NR vs 3 yrs p < 0.0001 Overall survival 3.5 yr 91% vs 84% p = 0.029 MCP ± R 2 PFS NR vs 29 mo 4 yr 87% vs 74% p < 0.0001 p = 0.0096 CHOP ± R 3 TTF NR vs 31 mo p = 0.0006 CVP ± R 4 TTP 34 mo vs 15 mo p < 0.0001 2 yr 95% vs 90% p = 0.016 4 yr 83% vs 77% p = 0.0290 1. Foussard C, et al. J Clin Oncol 2006; 24:Abstract 7508. 2. Herold M, et al. J Clin Oncol 2007; April 9 (Epub). 3. Hiddemann W, et al. Blood 2005; 106:3725 3732. 4. Marcus R, et al. Blood 2006; 108:Abstract 481.

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

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

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

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

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

Bendamustine B-R vs CHOP-R Toxicidade B-R CHOP-R Neutropenia G3-4 (%) 10,7 46,5 Alopecia (%) 15 G1 62 Infecção 95 121 Neuropatia Periférica 18 73 Rash 42 23 Rummel MJ et al ASH 2009 abst 405

PFS by subentities for R-bendamustine vs R-CHOP 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 Follicular 0.8 B-R 0.7 p = 0,0281 0.6 0.5 Follicular 0.4 0.3 p = 0,0281 0.2 0.1 0 0.0 12 24 36 48 60 72 0 12 24 36 48 60 72 Marginal zone Marginal zone B-R CHOP-R CHOP-R 1.0 0.9 p = 0.6210 0.8 p = 0.6210 0.7 B-R 0.6 B-R 0.5 CHOP-R 0.4 0.3 0.2 0.1 0.0 0 120 24 12 36 24 36 48 48 60 60 72 72 CHOP-R 1.0 Mantle cell 0.9 0.8 1.0 0.9 Mantle p = 0,0146 cell 0.7 0.8 0.6 p = 0,0146 0.7 0.5 0.6 0.4 0.5 B-R 0.3 0.4 CHOP-R B-R 0.20.3 0.1 CHOP-R 0.2 0.00.1 0.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Waldenström 1.0 0.91.0 Waldenström 0.8 0.9 0.8 0.7 0.7 0.6 p = 0.0024 B-R 0.6 B-R 0.5 0.5 0.4 0.4 0.3 0.3 p = 0.0024 0.2 0.2 0.1 0.1 0.0 0.0 0 0 12 12 24 24 36 48 60 60 72 72 CHOP-R CHOP-R (ASH 2009, Abstract 405, Rummel et al)

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

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

LNH baixo grau Stanford Sobrevida 100 Percentage survival 80 60 40 20 1987 1992 1976 1986 1960 1975 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (years) Horning SJ. Semin Oncol 1993;20(5 Suppl. 5):75 88

Fisher RI, et al. J Clin Oncol 2005; 23:8447 8452. Fisher, R. I. et al. J Clin Oncol; 23:8447-8452 2005

Overall survival improvement with rituximab in FL 1.0 GLSG study NHL 2000 Survival probability 0.8 0.6 0.4 0.2 GLSG study NHL 1996 p < 0.0001 0.0 0 12 24 36 48 60 72 Number of patients at risk: NHL 1996 NHL 2000 Time (months) 538 485 457 419 386 332 794 621 440 250 108 8 242 0 84 96 108 120 125 46 0 Hiddemann W, et al. Blood 2006; 108:Abstract 483.

Overall survival according to treatment regimen Liu, Q. et al. J Clin Oncol; 24:1582-1589 2006

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

Linfomas de Baixo Grau Manutenção

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

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

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;103:4416 23

SAKK35/98: event-free survival in previously untreated or relapsed indolent NHL 1.0 Probability 0.8 0.6 0.4 Prolonged treatment (n=73): median 23.2 months 0.2 0 p=0.024 Observation (n=78): median 11.8 months 0 6 12 18 24 30 36 42 48 54 Months since start of treatment Ghielmini M, et al. Blood 2004;103:4416 23

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

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)

(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; 27:1607-1614 2009

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; 27:1607-1614 2009

EORTC 20981 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

Progression-free survival (%) Intergroup phase III trial: PFS from second randomization all patients 100 90 80 70 60 50 40 30 20 10 0 Overall log-rank test: p<0.0001 Hazard ratio: 0.40 MabThera maintenance median: 51.6 months Observation median: 15.0 months 0 1 2 3 4 5 Years O N Number of patients at risk Treatment 110 167 90 42 17 5 Observation 66 167 126 86 47 12 MabThera

Intergroup phase III trial: PFS from second randomization by induction regimen Subgroups according to induction treatment Progression-free survival (%) 100 90 80 70 60 50 40 30 20 10 0 Progression-free survival after CHOP Overall log-rank test: p<0.0001; HR: 0.30 0 1 2 3 4 5 Years Median 42.0 months Median 11.6 months O N Number of patients at risk : Treatment 55 69 31 11 4 1 Observation 32 76 61 38 20 4 MabThera Progression-free survival (%) 100 90 80 70 60 50 40 30 20 10 0 Progression-free survival after R-CHOP Median 51.9 months Median 23.1 months Overall log-rank test: p=0.004; HR: 0.54 0 1 2 3 4 5 Years O N Number of patients at risk : Treatment 55 98 59 31 13 4 Observation 34 91 65 48 27 8 MabThera

Overall survival (%) Intergroup phase III trial: overall survival from second randomization 100 90 80 70 60 50 40 30 20 10 Overall log-rank test: p=0.011 HR: 0.52 MabThera maintenance 3 yrs 85.1% Observation 3 yrs 77.1% 0 0 1 2 3 4 5 6 Years O N Number of patients at risk : Treatment 39 167 148 99 50 14 2 Observation 23 167 155 112 69 19 4 MabThera

EORTC 20981 6 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

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)

Advantage for rituximab maintenance over observation in response duration and overall survival Response duration R-maintenance vs observation after FCM p-value p=0.0006 R-maintenance vs observation after R-FCM R-maintenance vs observation after R-FCM FL MCL p=0.0010 p=0.0346 p=0.0489 Overall survival R-maintenance vs observation after R-FCM p-value p=0.0562

R manutenção Linfoma. Folicular R-FCM indução Response Duration Forstpointner R et al. Blood 2006;108:4003-4008

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 12 23 mo Minnie Pearl 3* Ph. II 2 nd line Rituximab PFS 7 31 mo ECOG 1496 4 Ph. III 1 st line CVP PFS 18 50 mo EORTC 20981 5 Ph. III 2 nd line CHOP ± R PFS 15 51 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; 20:4461 4467. 2. Ghielmini M, et al. Blood 2004; 103:4416 4423. 3. Hainsworth JD, et al. J Clin Oncol 2005; 23:1088 1095. 4. Hochster HS, et al. Proc Am Soc Clin Oncol 2004; 22:Abstract 6502. 5. van Oers M, et al. Blood 2004; 104:Abstract 586. 6. Hiddemann W, et al. Proc Am Soc Clin Oncol 2005; 23:Abstract 6527.

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???

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

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

Primary endpoint (PFS) met at the planned interim analysis Rituximab maintenance significantly reduced the risk of progression by 50% Progression-free rate 1.0 0.8 0.6 0.4 0.2 0 Patients at risk stratified HR=0.50 95% CI 0.39; 0.64 p<.0001 Time (months) 82% 0 6 12 18 24 30 36 505 513 66% 472 443 336 230 103 18 469 411 289 195 82 15 Rituximab maintenance N=505 Observation N=513

Safety during rituximab maintenance 100 Patients (%) 80 60 40 Observation (n = 508) Rituximab maintenance (n = 501) 20 0 35 52 Any adverse event 22 37 Grade 2 infections 23 <1 16 <1 4 <1 4 Grade 3/4 adverse events Grade 3/4 neutropenia Grade 3/4 infections

Benefits of rituximab maintenance seen in sub-groups evaluated Category Subgroup Hazard ratio N Hazard ratio* 95% CIs All All 1018 0.49 0.38 0.64 Age < 60 60 624 394 0.45 0.59 0.33 0.62 0.39 0.90 FLIPl Index FLIPl 1 FLIPl = 2 FLIPl 3 216 370 431 0.38 0.39 0.61 0.19 0.77 0.25 0.61 0.43 0.67 Induction R-CHOP Chemotherapy R-CVP R-FCM 768 222 28 0.43 0.69 0.51 0.31 0.59 0.44 1.08 0.13 2.07 Response to Induction CR/CRu PR 721 290 0.52 0.45 0.38 0.70 0.29 0.72 0 1 2 3 Favors maintenance Favors observation * Non-stratified analysis

PRIMA impacto do regime de indução R-CHOP R-CVP R-FCM RR 92,8 84,7 75 CR/Cru 67,2 53 61,4 SAE 23 22 17 Neutropenia febril 2 0 11 Lugano 2011 abst 022

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 59,6 50 64,3 95,6 93,7 74,5 95,2 89,9 100 R-CHOP Melhor Taxa de Resposta e PFS Efeito mais substancial da manutenção

LNH 7-2008 The Maintain Study N=591 Observação B-R + R m 2 anos Rituximabe Manutenção 2 anos

RECIDIVAS

Sobrevida global LNH baixo grau TMO alogênico condicionamento clássico 1.00 Percent survival 0.75 0.50 0.25 N = 394 0.00 0 5 10 15 Years EBMT registry

CUP Trial Sobrevida Global Transplante Autólogo

Remission duration of all patients HD SCT St Bart s TBI Rohatiner, A. Z.S. et al. J Clin Oncol; 25:2554-2559 2007

EBMTR Linfoma Folicular Transplante Autólogo PFS Montoto et al Leukemia 2007

EBMTR Linfoma Folicular Transplante Autólogo OS Montoto et al Leukemia 2007

EBMTR Linfoma Folicular Transplante Autólogo Montoto et al Leukemia 2007

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

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

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 %

Linfoma do Manto Atenção ao envolvimento TGI

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

Linfoma do Manto: defeito no controle do ciclo celular e da resposta ao dano do DNA Nogai H et al. JCO 2011;29:1803-1811

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

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

Overall survival according to the combined biologic index (MIPIb) in 220 patients with Ki-67 available. 0.03535 times age (years) + 0.6978 (if ECOG > 1) + 1.367 times log10(ldh/uln) + 0.9393 times log10(wbc count) + 0.02142 times Ki-67 (%). EMCL network calculator Hoster E et al. Blood 2008;111:558-565

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

Combination chemotherapy MCL (series with n = 26-62) Regimen RR (%) EFS (mos) 2yOS (%) CVP 60-84 10-20 45-65 CHOP 75-88 7-21 60-76 MCP 63-73 13-15 85 R-CHOP 94-96 17-20 76 R-MCP 71 18 - Ghielmini and Zucca, Blood 2009

Linfoma do. Manto TTF GLSG Lenz G et al. JCO 2005;23:1984-1992

. R manutenção Pós R-FCM Linfoma do Manto Response Duration Forstpointner R et al. Blood 2006;108:4003-4008

PFS by subentities for R-bendamustine vs R-CHOP 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 Follicular 0.8 B-R 0.7 p = 0,0281 0.6 0.5 Follicular 0.4 0.3 p = 0,0281 0.2 0.1 0 0.0 12 24 36 48 60 72 0 12 24 36 48 60 72 Marginal zone Marginal zone B-R CHOP-R CHOP-R 1.0 0.9 p = 0.6210 0.8 p = 0.6210 0.7 B-R 0.6 B-R 0.5 CHOP-R 0.4 0.3 0.2 0.1 0.0 0 120 24 12 36 24 36 48 48 60 60 72 72 CHOP-R 1.0 Mantle cell 0.9 0.8 1.0 0.9 Mantle p = 0,0146 cell 0.7 0.8 0.6 p = 0,0146 0.7 0.5 0.6 0.4 0.5 B-R 0.3 0.4 CHOP-R B-R 0.20.3 0.1 CHOP-R 0.2 0.00.1 0.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Waldenström 1.0 0.91.0 Waldenström 0.8 0.9 0.8 0.7 0.7 0.6 p = 0.0024 B-R 0.6 B-R 0.5 0.5 0.4 0.4 0.3 0.3 p = 0.0024 0.2 0.2 0.1 0.1 0.0 0.0 0 0 12 12 24 24 36 48 60 60 72 72 CHOP-R CHOP-R (ASH 2009, Abstract 405, Rummel et al)

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

R-CHOP vs R-FC + R manutenção Idosos! R-CHOP R-FC p RR % 87 78 0,0581 CR % 38 34 OS m 64 38 0,0117

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

Intensification with Ara-C (series with n = 25 97) RR (%) CR (%) Hyper CVAD/MTX-AraC 92 40-70 R-Hyper CVAD/MTX-AraC 32-97 53-97 CHOP / DHAP 92 84 R-CHOP / R-DHAP 95 61 Toxic deaths: 0-8% Severe infections: 5-30% Severe thrombocytopenia: 30-80% Ghielmini and Zucca, Blood 2009

The role of high-dose cytarabine in MCL p=0.0382 (one sided sequential test) Hermine et al., ASH 2010

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

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

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

R-CHOP/R-DHAP TAMO Jovens! R-CHOP R-DHAP RR % 90 94 p 0,19 CR/Cru % 40 55 p 0,012 TAMO % 79 77 CR TAMO % 62 61 TTTF m 49 NR p 0,0384 HR 0,68 OS 3 anos 79 80

Novas Drogas Bortezomib Lenalidomide Temsirolimus Everolimus N RR CR EFS 155 33% 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

. Bortezomib Fase II Linfoma do Manto Refratário e Recidivado N 141 Fisher R I et al. JCO 2006;24:4867-4874

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

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

OBRIGADO