Linfomas Foliculares

(1)

Linfomas Foliculares

VI “Board Review” Hematologia

Dr Jacques Tabacof

Centro de Oncologia e Hematologia Hospital Israelita Albert Einstein

(2)

Linfomas Não-Hodgkin Células B

CLL/SLL (12%) PMBL (3%) High-grade B, NOS (2.5%) BL (0.8%) Splenic MZ (0.9%) Nodal MZ (2%) Lymphoplasmacytic (1.4%)

Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

(4th _{edition). Lyon, France: IARC Press, 2008.}

DLBCL (37%) FL (29%) MALT (9%) MCL (7%) (12%) BL = Burkitt’s lymphoma

MALT = mucosal associated lymphoid tissue MZ = marginal zone SLL = small lymphocytic leukaemia

NOS = not otherwise specified

(3)

Linfomas: Originam-se de Linfócitos em diferentes estágios de diferenciação

Nogai H et al. JCO 2011;29:1803-1811

Somatic Hypermutation

(4)

t(14;18) evento iniciador na patogênese molecular dos Linfomas Foliculares

(5)

Linfomas Foliculares

• 30 % dos LNH

• Incidência 4:100000 • Idade mediana 60 anos • Sintomas B raros

CD10

• Sintomas B raros • Graus I II IIIa e IIIb

• Citogenética: t(14;18) 85 % • BCL-2 proximo a gene IgH • Hiperexpressão bcl-2

(6)

Linfoma Foliculares

• Diagnosticado em estadios avançados

• Sensíveis a Quimioterapia e Radioterapia • Recidivas são frequentes

• Respostas cada vez mais curtas • 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 1.0 0.4 0.8 0.6 P ro b a b il it y o f s u rv iv a l Good

Solal-Celigny P, et al. Blood 2004; 104:1258–1265

Risk group Factors (n)

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% Stage III/IV Haemoglobin < 12 g/dl 0 0 0.2 0 12 24 36 48 60 72 84 p < 0.0001 P ro b a b il it y o f s u rv iv a l Intermediate Poor Months

(8)

Mannikin used for counting the number of involved areas

(9)

FLIPI 2

Factors Independently Predictive for PFS

• β2-microglobulin higher than the upper

limit of normal

• Longest diameter of the largest • 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

(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.

(11)

Linfoma Não-Hodgkin Baixo Grau

Estadios Iniciais

• 10-20 % doença localizada (estadios I e II) • Tratamento Standard:

– Radioterapia Campo Envolvido – Radioterapia Campo Envolvido – 30-50 % 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 82 28 % 52 % BNLI 208 47 % 64 % (est I) PMH 190 53 % 58 % (12 a) PMH 190 53 % 58 % (12 a) Stanford 177 44 % 64 % MDACC 80 41 % 43 % (15 a) Royal M 58 43 % 79 %

(13)

Tentativas de Otimização

• Estadiamento com Laparotomia • Campos de Irradiação Extensos • Campos de Irradiação Extensos

– “Extended-Field”

– Irradiação Linfóide Total

(14)

Linfoma Não-Hodgkin Baixo Grau

Estadios Iniciais

Conclusões

• Situação Rara

• Tratamento standard Radioterapia

Campo Envolvido

• Dose 30-40 Gy • Dose 30-40 Gy

• Curabilidade 50 % 10 anos

• Tratamentos sistêmicos utilizados em

alguns centros

• Pacientes selecionados podem ser

(15)

Opções de Tratamento Estadios Avançados

• Observação cuidadosa “watch and Wait” • Agentes alquilantes • Fludarabina • Rituximabe • CVP; CHOP • 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

(17)

Watch & wait versus immediate treatment for

asymptomatic advanced stage indolent NHL

Overall survival Observation (n = 151) Chlorambucil (n = 153) 100 80 60 40 C u m u la ti v e s u rv iv a l (% ) 20 0 0 Years 4 8 12 16 20 24 C u m u la ti v e s u rv iv a l (% )

Ardeshna KM, et al. Lancet 2003; 362:516–522

Median 5-year 10-year 15-year

Chlorambucil 5.9 years 57% 35% 21%

(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

(19)

ARM A

Watchful waiting

Watch and wait: Study design

• Primary endpoints:

– Time to initiation of new therapy (chemotherapy or radiotherapy)

– Effect on quality of life

ARM A Watchful waiting R A ARM B R-mono 375 mg/m2 weekly x 4 ARM C R-mono 375 mg/m2 weekly x 4 + maintenance q2mo for 2 years

DISCONTINUED • Asymptomatic stage 2, 3 or 4 FL • Grades 1, 2 & 3a • Adequate bone marrow reserve ARM B R-mono 375 mg/m2 weekly x 4 ARM C R-mono 375 mg/m2 weekly x 4 + maintenance q2mo for 2 years

X

Total planned enrolment: 360 patients

A N D O M I S E

Ardeshna KM, et al. Blood 2010;116:Abstract 6.

Progressive disease requiring therapy

stops protocol treatment

(20)

Time to initiation of new therapy (TTINT) P ro p o rt io n o f p a ti e n ts n e w t re a tm e n t in it ia te d 0.5 0.6 0.7 0.8 0.9 1.0 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

P ro p o rt io n o f p a ti e n ts w it h n o n e w t re a tm e n t in it ia te d

Years from randomisation

1 2 3 4 5

% not requiring Rx at 3 yrs W+W = 48% R4 = 80% R4+RM = 91% 19 192 19 84 83 187 Events Totals W+W R4 R4 + M 0.0 0.1 0.2 0.3 0.4 0.5 0

(21)

Overall Survival % o f p a ti e n ts a li v e 3yr OS = 95% 0.5 0.6 0.7 0.8 0.9 1.0 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

% o f p a ti e n ts a li v e

Years from randomisation

1 2 3 4 5 8 192 4 84 9 187 Events Totals W+W R4 R4 + M 0.0 0.1 0.2 0.3 0.4 0.5 0

(22)

“Watch and Wait”

Motivos a favor

• Observar ritmo da doença

• Não piora sobrevida (tratamentos

antigos)

• Tempo para tratamento 2 anos • 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 • Tratar pessoas que não precisam é

prática comum em oncologia

• Dogma oncológico: menor volume

maior chance de cura

• Rituximabe aumento o tempo para

(24)

LNH baixo grau

Stanford Sobrevida

P e rc e n ta g e s u rv iv a l 100 80 60 1987–1992 P e rc e n ta g e s u rv iv a l 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (years) 1976–1986 1960–1975

(25)

Clorambucil + Prednisona vs. CHOP

LNH indolente sintomático

• 259 pacientes estadios avançados, não

tratados, sintomáticos

• ORR: Ch/P 36% versus CHOP 60%

Kimby E, et al. Ann Oncol 1994;5(Suppl.2):67–71

• 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)

(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

• 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 0.8 0.6 P ro p o rt io n d is e a s e -f re e 1.0 0.8 0.6 P ro p o rt io n s u rv iv in g Cyclophosphamide CHOP + bleomycin Cyclophosphamide CHOP + bleomycin DFS OS

Peterson BA, et al. J Clin Oncol 2003;21:5–15

0.6 0.4 0.2 0 P ro p o rt io n d is e a s e 0.6 0.4 0.2 0 P ro p o rt io n s u rv iv in g 0 2 4 6 8 10 12 14 16 18 Years from entry

0 2 4 6 8 10 12 14 16 18 Years from entry

(28)

Rituximab: Anticorpo Quimérico

Humano/Murino

Regão variável murina liga CD 20

Região Constante kappa Humana

Dominio Fc Humano IgG₁sinergia com mecanismos efetores humanos

IgG1 Quimérico

(29)

MabThera agente único Linfoma Folicular

Pacientes Previamente tratados

Reference n OR (%) CR (%) Duration of response (months) Maloney DG, 1997 34 50 9 10.2 McLaughlin P, 1998 118 60 6 13.0 Duração da resposta (meses) Referência RG RC 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 50–60 5–10 12 Geral

(30)

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

26

20 40

20 0

(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)

(32)

Overall survival CVP or R-CVP

(33)

OS after start of therapy for CHOP and R-CHOP

P 0 p = 0,016

Hiddemann, W. et al. Blood 2005;106:3725-3732

(34)

Overall survival MCP or R-MCP

(35)

FL2000 study with a 5-year median follow-up

(36)

Indução com Quimioterapia e Rituximab Aumenta Sobrevida

Induction regimen Outcome (median) Overall survival

CHVP ± R + IFN-α1 _EFS _{NR vs 3 yrs}

p < 0.0001

3.5 yr 91% vs 84%

p = 0.029

MCP ± R2 _PFS _{NR vs 29 mo} _{4 yr} _{87% vs 74%}

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.

MCP ± R2 _PFS _{NR vs 29 mo} p < 0.0001 4 yr 87% vs 74% p = 0.0096 CHOP ± R3 _TTF _{NR vs 31 mo} p = 0.0006 2 yr 95% vs 90% p = 0.016 CVP ± R4 _TTP _{34 mo vs 15 mo} p < 0.0001 4 yr 83% vs 77% p = 0.0290

(37)

(38)

R-CVP vs R-CHOP vs R-FM para Linfoma Folicular Avançado Sem Tratamento Prévio

(39)

(40)

(41)

Bendamustine was synthesized as a unique

chemical structure combining an alkylating group

BENDAMUSTINE

with a purine-like benzimidazole ring in 1963

The alkylating group contains mechlorethamine,

which confers alkylating properties

The benzimidazole component contains a

(42)

Bendamustine

B-R vs CHOP-R • 549 pacientes sintomáticos (FL 55% MCL 18% e Indolentes 27%) • Estadio IV 78 % B-R CHOP-R 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

(43)

Bendamustine

B-R vs CHOP-R • Toxicidade B-R CHOP-R Neutropenia G3-4 (%) 10,7 46,5 Neutropenia G3-4 (%) 10,7 46,5 Alopecia (%) 15 G1 62 Infecção 95 121 Neuropatia Periférica 18 73 Rash 42 23

(44)

PFS by subentities for

R-bendamustine vs R-CHOP

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 0 12 24 36 48 60 72 0.0 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024

(ASH 2009, Abstract 405, Rummel et al)

0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 0 12 24 36 48 60 72 0.0 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024 0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024 0 12 24 36 48 60 72 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024

(45)

Bendamustina-Rituximabe vs

CHOP-Rituximabe em Linfomas Indolentes

(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

P e rc e n ta g e s u rv iv a l 100 80 60 1987–1992 P e rc e n ta g e s u rv iv a l 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (years) 1976–1986 1960–1975

(48)

Fisher RI, et al. J Clin Oncol 2005; 23:8447–8452.

(49)

S u rv iv a l p ro b a b il it y 0.6 0.8 1.0 GLSG study NHL 2000 GLSG study NHL 1996

Overall survival improvement

with rituximab in FL

24

Hiddemann W, et al. Blood 2006; 108:Abstract 483.

S u rv iv a l p ro b a b il it y Time (months) 0.0 0.2 0.4 0 12 36 48 60 72 p < 0.0001

Number of patients at risk:

NHL 1996 NHL 2000 538 485 457 419 386 332 794 621 440 250 108 8 242 0 125 46 0 84 96 108 120

(50)

Overall survival according to treatment regimen

(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 ?

(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 • 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)

n=151 n=202

Observation

R

SAKK 35/98 study design

MabThera 375mg/m² every 2 months x 4 PD off study Prolonged treatment MabThera 375mg/m² weekly x 4

R

SD, PR, CR

(56)

SAKK35/98: event-free survival in previously untreated or relapsed indolent NHL

1.0 0.8 0.6 P ro b a b il it

y Prolonged treatment (n=73): median 23.2 months

0.4

0.2

0

0 6 12 18 24 30 36 42 48 54

Months since start of treatment

P ro b a b il it y p=0.024

Observation (n=78): median 11.8 months

(57)

SAKK 35/98

Sobrevida Livre de Eventos

(58)

CVP ± maintenance MabThera (ECOG 1496): study treatment Observation (Obs) Maintenance rituximab (MR) CVP R A N D O M IS R E S T A G CR, PR, SD Stratify: histology, residual disease

C = cyclophosphamide 1,000mg/m2 i.v. day 1

V = vincristine 1.4mg/m2 (maximum = 2) i.v. day 1 P = prednisone 100mg/m2 p.o. days 1–5

Repeat every 21 days; best response + two cycles (6–8) MR = MabThera 375mg/m2 weekly x 4

Start 4 weeks after CVP; every 6 months for 2 years E

G E

(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)

Hochster, H. et al. J Clin Oncol; 27:1607-1614 2009

(B) PFS for 228 evaluable follicular lymphoma patients randomly assigned to

(60)

A. OS 311 evaluable indolent lymphoma patients randomly assigned to maintenance rituximab (MR; n = 158) or observation (OBS; n = 153)

Hochster, H. et al. J Clin Oncol; 27:1607-1614 2009

B. OS for 288 evaluable follicular lymphoma patients randomly assigned to MR

(61)

R A N D O M CHOP every 21 days (maximum six cycles)

EORTC 20981 phase III trial:

Resistant/Relapsed

Observation R A N D O M M I S A T I O N six cycles) MabThera + CHOP every 21 days (maximum six cycles) MabThera maintenance* CR PR

*375mg/m2 _{every 3 months for 2 years or until relapse}

M I S A T I O N

(62)

Intergroup phase III trial: PFS from second randomization – all patients

100 90 80 70 60 50 MabThera maintenance median: 51.6 months fr e e s u rv iv a l (% )

Overall log-rank test: p<0.0001 Hazard ratio: 0.40

O N Number of patients at risk

110 167 90 42 17 5 Observation 66 167 126 86 47 12 MabThera Treatment 50 40 30 20 10 0 0 1 2 3 4 5 Years Observation median: 15.0 months P ro g re s s io n -f re e s u rv iv a l (% )

(63)

Intergroup phase III trial: PFS from second randomization – by induction regimen

Progression-free survival after CHOP 100 90 Progression-free survival after R-CHOP 100 90

Subgroups according to induction treatment

fr e e s u rv iv a l (% ) fr e e s u rv iv a l (% )

Overall log-rank test: p<0.0001; HR: 0.30

O N Number of patients at risk :

55 69 31 11 4 1 Observation 32 76 61 38 20 4 MabThera Treatment 90 80 70 60 50 40 30 20 10 0 Years 0 1 2 3 4 5

Overall log-rank test: p=0.004; HR: 0.54

after R-CHOP

O N Number of patients at risk :

55 98 59 31 13 4 Observation 34 91 65 48 27 8 MabThera Treatment 90 80 70 60 50 40 30 20 10 0 Years 0 1 2 3 4 5 Median 42.0 months

Median 11.6 months Median 23.1 months

Median 51.9 months P ro g re s s io n -f re e s u rv iv a l (% ) P ro g re s s io n -f re e s u rv iv a l (% )

(64)

Intergroup phase III trial: overall survival from second randomization

100 90 80 70 60 50

MabThera maintenance 3 yrs 85.1%

O v e ra ll s u rv iv a l (% )

Overall log-rank test: p=0.011 HR: 0.52 O N 39 167 _Observation 23 167 MabThera Treatment 50 40 30 20 10 0 Years 0 1 2 3 4 5 6

Number of patients at risk :

148 99 50 14 2 155 112 69 19 4 Observation 3 yrs 77.1% O v e ra ll s u rv iv a l (% )

(65)

• EFS

– Rituximab maintenance 3.7 years

– Observation arm 1.3 years

– p<0.0001; hazard ratio 0.55 EORTC 20981 6 years follow up – 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

Fludarabine Fludarabine

OS was significantly increased in the R-FCM induction arm

compared to FCM alone (p=0.031) – all subsequent patients received R-FCM induction PR, CR Fludarabine Cyclophosphamide Mitoxantrone Cyclophosphamide Mitoxantrone + rituximab 4 x rituximab (month 3)

Watch and wait

R

(67)

Advantage for rituximab maintenance over observation in response duration and overall

survival

Response duration p-value

R-maintenance vs observation after FCM R-maintenance vs observation after R-FCM

p=0.0006 p=0.0010 R-maintenance vs observation after R-FCM

R-maintenance vs observation after R-FCM FL

MCL

p=0.0346 p=0.0489

Overall survival p-value

(68)

.

R manutenção Linfoma Folicular R-FCM indução

Forstpointner R et al. Blood 2006;108:4003-4008

(69)

Study/group Trial design Setting Study induction Rituximab maintenance Minnie Pearl1* _{Ph. II} ₁st _line _Rituximab _{OR 74%,PFS 37mo} SAKK 35/982 _{Ph. III} ₁st_/2nd _line _Rituximab _{EFS 12}_→_{23 mo}

Studies of rituximab maintenance

therapy in follicular NHL

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.

Minnie Pearl3*† _{Ph. II} ₂nd _line _Rituximab _{PFS 7}_→_{31 mo} ECOG 14964 _{Ph. III} ₁st _line _CVP _{PFS 18}_→_{50 mo} EORTC 209815 _{Ph. III} ₂nd _line _{CHOP ± R} _{PFS 15}

→ 51 mo

GLSG6‡ _{Ph. III} ₂nd _line _{FCM ± R} _{RD 19}

→ NR (3y)

* Included patients with small lymphocytic lymphoma

†_{Randomized – maintenance versus retreatment} ‡_{Included patients with MCL}

(70)

(71)

Manutenção

• R-QT superior a QT de “indução”

• R manutenção eficaz após QT e após

R-CHOP, R-FCM em segunda linha R-CHOP, R-FCM em segunda linha

• Papel da Manutenção em pacientes

tratados com R-QT em primeira linha???

(72)

PRIMA: study design

Rituximab maintenance 375 mg/m2 every 8 weeks for 2 years‡ CR/CRu Immunochemotherapy 8 x Rituximab + High tumor burden INDUCTION MAINTENANCE Registration PD/SD off study Observation‡ CR/CRu PR Random 1:1* + 8 x CVP or 6 x CHOP or 6 x FCM tumor burden untreated follicular lymphoma

* Stratified by response after induction, regimen of chemo, and geographic region

‡ _{Frequency of clinical, biological and CT-scan assessments identical in both arms}

(73)

R-CHOP N = 885 * 15 pts in 3 sites closed prematurely Patients evaluable (N = 1202)* R-CVP N = 272 Patients registered: N = 1217 R-FCM N = 45 In d u c ti o n

9 pts did not receive chemo

147 pts withdrew during or at

Patient disposition

Randomized N = 769 Randomized N = 222 Randomized N = 28 Observation N = 513 Rituximab N = 505

‡ _{1 pt died during the}

randomization process M a in te n a n c e 147 pts withdrew during or at the end of induction (failure to respond; toxicity)

28 pts failed to be randomized

Patients randomized: N = 1018‡

(74)

Primary endpoint (PFS) met at the planned interim analysis

Rituximab maintenance significantly reduced the risk of progression by 50% Rituximab maintenance N=505 Observation fr e e r a te _0.8 0.6 1.0 82% stratified HR=0.50 95% CI 0.39; 0.64 p<.0001 Time (months) Observation N=513 6 0 12 18 24 30 36 P ro g re s s io n -f re e r a te 0.6 0.4 0.2 0 66% Patients at risk 505 513 472 443 336 230 103 18 469 411 289 195 82 15

(75)

Rituximab maintenance (n = 501) Observation (n = 508)

Safety during rituximab maintenance

P a ti e n ts ( % ) 100 80 60 52 37 Any adverse event Grade 3/4 neutropenia Grade 3/4 infections Grade ≥2 infections P a ti e n ts ( % ) 40 20 0 <1 4 <1 4 23 Grade 3/4 adverse events <1 35 22 16

(76)

Benefits of rituximab maintenance seen in sub-groups evaluated

Subgroup Hazard ratio

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

(77)

PRIMA

impacto do regime de indução

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

(78)

PRIMA : Impacto do regime de indução 3 ANOS (%) R-CHOP R-CVP R-FCM PFS Manutenção 78,6 61,6 78,6 PFS Observação 59,6 50 64,3 Observação OS Manutenção 95,6 93,7 74,5 OS Observação 95,2 89,9 100

R-CHOP Melhor Taxa de Resposta e PFS

(79)

LNH 7-2008

The Maintain Study

N=591 Observação B-R + R m 2 anos Observação Rituximabe Manutenção 2 anos

(80)

(81)

Sobrevida global LNH baixo grau

TMO alogênico condicionamento clássico

N = 394 0.75 1.00 P e rc e n t s u rv iv a l EBMT registry 0 5 10 15 0.00 0.25 0.50 P e rc e n t s u rv iv a l Years

(82)

CUP Trial Sobrevida Global

Transplante Autólogo

(83)

Remission duration of all patients HD SCT St Bart’s TBI

(84)

EBMTR Linfoma Folicular Transplante Autólogo PFS

(85)

EBMTR Linfoma Folicular Transplante Autólogo OS

(86)

EBMTR Linfoma Folicular Transplante Autólogo

(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

(88)

Conclusões II

• Transplante Alogênico de MO é

potencialmente curativo

• Quimioterapia em Altas Doses (TAMO) • Quimioterapia em Altas Doses (TAMO)

tem papel em casos selecionados – Recidiva quimiossensível

(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 – 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

(91)

Tipos Histológicos MCL

Typical MCL _{Blastoid Variant}

(92)

Linfoma do Manto: defeito no controle do ciclo celular e da resposta ao dano do DNA

(93)

Linfoma do Manto CCND1 negativo

Existe !

• Expressão Gênica semelhante a CCND1 + • Alta expressão e translocações de

• Alta expressão e translocações de

CCND2 e CCND3

– CCND2 e D3 expressas em outros LNH

(94)

Linfoma do Manto Indolente Existe !

• Fatores Prognósticos Favoráveis

– Ki67 baixo

– Estadio Limitado – Estadio Limitado

• Apresentação não-nodal,

esplenomegalia, fase leucêmica

(95)

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 (%).

Hoster E et al. Blood 2008;111:558-565

(96)

MCL treatment modalities

• Single agent chemotherapy

• Polychemotherapy regimens

(+/-doxorubicin)

• Purine analogues based • Purine analogues based

• Intensive regimens (with HD-AraC) • Monoclonal antibodies

• Auto and Allo BMT

(97)

Combination chemotherapy MCL

(series with n = 26-62)

Regimen RR (%) EFS (mos) 2yOS (%)

CVP 60-84 10-20 45-65 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 RMCP 71 18

(98)

.

Linfoma do Manto TTF GLSG

(99)

.

R manutenção Pós R-FCM Linfoma do Manto

Response Duration

(100)

PFS by subentities for

R-bendamustine vs R-CHOP

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Follicular p = 0,0281 Mantle cell p = 0,0146 B-R B-R CHOP-R CHOP-R 0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 0 12 24 36 48 60 72 0.0 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024

(ASH 2009, Abstract 405, Rummel et al)

0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 0 12 24 36 48 60 72 0.0 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024 0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0.0 0.0 0 12 24 36 48 60 72 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024 0 12 24 36 48 60 72 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Marginal zone p = 0.6210 Waldenström B-R B-R CHOP-R CHOP-R p = 0.0024

(101)

R-CHOP vs R-FC + R manutenção

Idosos ! > 60 anos

• MCL Network n = 559 > 60 anos • “Duas Randomizações” • “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 % 87 78 0,0581 RR % 87 78 0,0581 CR % 38 34 OS m 64 38 0,0117

(103)

R-CHOP vs R-FC + R manutenção

Idosos !

• Manutenção • Duração da Remissão – Rituximabe 51 m – 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 92 40-70 R-Hyper CVAD/MTX-AraC 32-97 53-97 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%

(105)

The role of high-dose cytarabine in MCL

p=0.0382 (one sided sequential test)

(106)

The Nordic trial of PBSCT in MCL

n = 160 Age < 66 MCL 2 R-maxi CHOP R-HD-AraC R-HD-AraC R-in-vivo purging BEAM MCL 1 maxi CHOP BEAM

(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

(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

(109)

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

(110)

N RR CR EFS Bortezomib 155 33% 8% 6m Lenalidomide 15 53% 20% 6m

Novas Drogas

Temsirolimus 54 22% 2% 5m Everolimus 35 20% 6% 5m

Fisher et al., JCO 2006

Habermann et al, BJH 2009 Hess et al, JCO 2009

(111)

.

Bortezomib Fase II Linfoma do Manto Refratário e Recidivado

N 141

(112)

Estadios I e II Linfoma do Manto BCCA 26 pacientes

(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)