tratamento do linfoma de hodgkin - abhh eventos · carl sternberg 1898 . dorothy reed 1902 . johns...
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Tratamento do Linfoma de Hodgkin Nelson Spector - UFRJ
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Thomas Hodgkin 1798-1866
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Ilustração usada por Hodgkin na sua apresentação original, feita em 1832 na Medical and Chirurgical Society, Londres
Gordon Museum, Guy’s Hospital, Londres
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Reavaliação dos pacientes estudados por Thomas Hodgkin (1832) feitas por Fox (1926), Symmers (1978) e Lennert (1987)
Gordon Museum, Guy´s Hospital, Londres
Paciente Diagnóstico
1. Tuberculose (+ doença de Hodgkin ?)
2. Doença de Hodgkin
3. Sífilis
4. Doença de Hodgkin
5. “Linfomatose sistêmica (linfocítica)”
6. Imunocitoma linfoplasmocitóide
7. Doença de Hodgkin ?
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Carl Sternberg 1898
Dorothy Reed 1902
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Johns Hopkins Medical School – Classe de 1900
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Cortesia da Dra. Elaine Jaffe
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Classical Hodgkin Lymphoma
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Henry Kaplan
William Allen Pusey
JAMA – março 1902
Wilhelm Röntgen – Raios X em 1895
Prêmio Nobel de Física em 1901
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Bari, 2 de dezembro de 1943
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83 mortes na 1ª semana – leucopenia grave
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JAMA 1946
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DeVitaVT. The consequences of the chemotherapy of Hodgkin’s Disease. Cancer 1981; 47:1-13.
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George Canellos
Vincent DeVita
Bruce Chabner 1970
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DeVita VT et al. Ann Int Med 1970; 73: 881-95
Longo DL et al. J Clin Oncol. 1986 4:1295-306.
MOPP
DeVitaVT. The consequences of the chemotherapy of Hodgkin’s Disease. Cancer 1981; 47:1-13.
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Causa do óbito em 2498 pacientes tratados em Stanford entre 1960-1995
Aisenberg A. Blood 1999; 93:761-79.
Doença de Hodgkin
Complicações do tratamento
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TOXICIDADE EFICÁCIA
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Fatores Prognósticos
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Idade ≥ 45 anos Sexo masculino Estádio IV Albumina < 4 g/dl Hemoglobina < 10,5 g/dl Leucócitos ≥ 15.000/mm3
Linfócitos < 600 ou < 8%
No fatores n SLP
0 7% 84% 1 22% 77% 2 29% 67% 3 23% 60% 4 12% 51% >5 7% 42%
Hasenclever D et al, NEJM 1998; 339:1506-14.
n=4695
Escore prognóstico para a Doença de Hodgkin avançada
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Escore prognóstico para a Doença de Hodgkin avançada
Hasenclever D et al, NEJM 1998; 339:1506-14.
SLP
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Gallamini et al JCO August 20, 2007
PET após o 2º ciclo de tratamento
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Tratamento
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Para fins de tratamento
Doença localizada (I-II) sem fatores de risco
Doença localizada (I-II) com fatores de risco
Doença avançada (III e IV, e IIB com gde massa ou doença extra-linfática)
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Doença localizada sem fatores de risco
Sintomas B VHS > 50 mm
Doença “bulky” > 3 áreas linfonodais Homens > 40 anos
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ABVD + RT
Milão Vancouver GHSG
Estádios IA, IB, IIA IA, IIA IA, IIA
Nº de pacientes 140 268 204
Acompanhamento mediano, meses 87 67 22
Ciclos de ABVD 4 2 2
RT IF/EF IF EF
SLP 95% 98% 96%
Sobrevida global 93% 97% 98%
Connors JM. J Clin Oncol 2005; Sept 10; 6400-8.
IF=campo envolvido EF=campo extendido
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CS I–II without risk factors
ABVD ABVD
30 Gy IF
ABVD ABVD
ABVD ABVD ABVD ABVD
ABVD ABVD ABVD ABVD
30 Gy IF 20 Gy IF 20 Gy IF
Engert A et al. N Engl J Med 2010;363:640-52.
Early Favorable Stage GHSG: HD10- Trial
N= 1370
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CS I–II without risk factors
ABVD ABVD
30 Gy IF
ABVD ABVD
ABVD ABVD ABVD ABVD
ABVD ABVD ABVD ABVD
30 Gy IF 20 Gy IF 20 Gy IF
Early Favorable Stage GHSG: HD10- Trial
Engert A et al. N Engl J Med 2010;363:640-52.
N= 1370
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CS I/II without RF*
ABVD
ABVD
ABV
ABV
AVD
AVD
AV
AV
30 Gy IF 30 Gy IF 30 Gy IF 30 Gy IF
*Large mediastinal mass; extranodal disease; high ERS; 3 or more areas involved
HD13 Trial for patients with early favourable stage
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Campos de radioterapia
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Campbell BA et al. J Clin Oncol 2008; 26:5170-5174.
Until 1996
Since 2001 1996-2001
BCCA – 325 patients
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Perspectivas
Estudos em andamento
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RANDOMIZAÇÃO
2 CICLOS DE ABVD 2 CICLOS DE ABVD
PET
IFRT 30
PET
PET NEGATIVO
PET POSITIVO
2 CICLOS ABVD E RT 30 Acompanhar
HD16: DOENÇA LOCALIZADA FAVORÁVEL
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Doença localizada com fatores de risco
Sintomas B VHS > 50 mm
Doença “bulky” > 3 áreas linfonodais Homens > 40 anos
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clinicaloptions.com/oncology Lymphomas
Intensified Chemo + Dose Reduced IF-RT in Early Unfavorable HL: GHSG HD11
Borchmann P, et al. ASH 2009. Abstract 717.
Inclusion criteria
– Stage I/IIA HL with large mediastinal mass, extranodal involvement, elevated erythrocyte sedimentation rate, and ≥ 3 involved nodal areas
Or
– Stage IIB HL with elevated erythrocyte sedimentation rate and ≥ 3 involved nodal areas
CSI, 11A with risk factors a-d, CS 11B with risk factors c, d
(a: large mediastinal mass; b: extranodal involvement; c: elevated ESR; d: ≥ 3 nodal areas)
Randomization
4x ABVD 4x ABVD 4x BEACOPP
4x BEACOPP
30 Gy IFRT
20 Gy IFRT
30 Gy IFRT
20 Gy IFRT
Arm A Arm B Arm C Arm D
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clinicaloptions.com/oncology Lymphomas
GHSG HD11: Results
Borchmann P, et al. ASH 2009. Abstract 717.
Primary endpoint: 5-yr estimated freedom from treatment failure
Free
dom
Fro
m T
reat
men
t Fai
lure
1.0 0.9 0.8 0.7 0.6 0.5
0.4 0.3
0.2 0.1
0 0 12 24 36
Mos 48 60 72 84 96 108
P = .654
5-Yr Estimate (95% CI) 4x ABVD: 85.3% (81.1% to 88.7%)
4x BEACOPP: 87.0% (82.8% to 90.2%)
ABVD + 30 Gy BEACOPP + 30 Gy
356 330 308 293 271 255 206 136 73 40 341 313 293 278 275 249 203 138 78 34
ABVD + 30 Gy BEACOPP + 30 Gy
Pts. at Risk, n
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Doença localizada desfavorável (“intermediária”)
Combinação quimio/radio é considerada
padrão: 4 ABVD+ 30 Gy IF-RT Resultados: 90% SLP em 5 anos 93% SG em 5 anos
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Blood 2004 6 ciclos de ABVD em ambos
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Localizada favorável: 2 ABVD + 20 Gy IF-RT
Localizada desfavorável: 4 ABVD + 30 Gy IF-RT Diretrizes do NCCN também admitem ABVD 6 ciclos sem RT
Padrão de tratamento da doença localizada fora de estudos clínicos
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Tratamento da Doença de Hodgkin avançada
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Protocolo
MOPP
ABVD
MOPP/ABVD
MOPP/ABV
RC (%)
84
81
89
84/97
SLD
68% em 10 anos 60% em 20 anos
64% em 3 anos
76% em 7 anos
77% em 7 anos
DH avançada Resultados terapêuticos
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CALGB Hodgkin’s disease Championship
Game Winner Loser
1st round MOPP x ABVD x MOPP-ABVD1 ABVD e MOPP-ABVD MOPP
2nd round MOPP-ABVD X MOPP/ABV2 MOPP/ABV MOPP-ABVD
Finals ABVD X MOPP/ABV3 ABVD MOPP/ABV
1. Canellos G et al. N Engl J Med 1992; 327:1478-84
2. Glick J et al. J Clin Oncol 1998; 16:19-26
3. Duggan DB et al. J Clin Oncol 2003; 21:607-14
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A
8 x COPP/ABVD
± RT
B
8 X BEACOPP
± RT
C
8 X BEACOPP++ ± RT
COPP/ABVD x BEACOPP x BEACOPP++
grande massa - 30 Gy massa residual - 40 Gy RT
randomização
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HD9- 10 ys FFTF by treatment arm
Log-rank tests:
A v B v C p<0.0001
A v B p=0.040
B v C p<0.0001
A v C p<0.0001
BEA esc
C/ABVD
82%
64%
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GHSG 2007 HD9
HD9-10 ys- OS by treatment arm
Log-rank tests:
A v B v C p=0.0005
A v B p=0.19
B v C p=0.0053
A v C p<0.0001
BEA esc
C/ABVD
86%
75%
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Perfil de efeitos colaterais
ABVD BEACOPPesc
Toxicidade pulmonar sim sim
Toxicidade hematológica 3-4
40% > 90%
Infecções 3-4 raro 22% (6%)
Infertilidade/ menopausa
não sim
Leucemias/MDS não/raro sim
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Perspectivas
Estudos em andamento
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A total of 550 patients (225 per treatment arm) will be accrued for this study within 5.5 years. Study Start Date: August 2002
Intergroup H34 20012: EORTC, GELA, NCI-Canada, Nordic LG, Australia
DH avançada
>3 fatores de risco
Idade < 60 anos
RANDOMI ZAÇÃO
8 x ABVD
4 x BEACOPPesc
4 x BEACOPPs
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Estudos com avaliação precoce da resposta por PET scan
UK RATHL ABVD. Escalar para BEACOPP se PET+. Se PET-, randomizar entre ABVD e ABV.
Italiano Escalar para transplante autólogo se PET+
US Intergroup ABVD. Escalar para BEACOPP se PET+.
GHSG HD15 e HD18
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Tratamento da resistência primária e secundária
Transplante autólogo
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Recaídas após transplante
• Inibidor de histona-deacetilases - panobinostate
• Brentuximabe vedotin
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Panobinostate • Histona-deacetilases mediam a acetilação e
deacetilação de aminoácidos em proteínas envolvidas na proliferação e sobrevida celular e angiogênese.
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Recaídas após transplante Tratamento Via Alvo N RC+RP Panobinostat Oral HiDAC 129 33 (26%)
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CD30 tem expressão densa e restrita às células de Reed-Sternberg no LH
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Recaídas após transplante Tratamento Via Alvo N RC+RP Panobinostat Oral HiDAC 129 33 (26%) MDX060 IV CD30 47 4(8%) SGN30 IV CD30 38 0(0%)
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Brentuximabe vedotin (SGN35)
• CD30 acoplado a uma tubulina citotóxica, a mono-metil-auristatina E (MMAE)
• Ligação covalente estável, apenas 2% de liberação da MMAE após incubação por 10 dias em plasma humano
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• > 70% tinham resistência primária • Todos em recaída pós-transplante autólogo • Mediana de tratamentos prévios = 4
• Redução de tumor em 95% • RC em 32%, RP em 42% • Desaparecimento de sintomas B em 83%
Brentuximabe vedotin (SGN35) Estudo fase II com 102 pacientes
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• Aprovado pelo FDA em 19/9/2011 • Indicações
– Linfoma de Hodgkin • Recaída pós-transplante autólogo ou • Recaída após pelo menos 2 tratamentos prévios,
em pacientes sem indicação para transplante autólogo
– Linfoma anaplásico de grandes células
Brentuximabe vedotin (SGN35)
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• Dose 1,8 mg/kg infusão de 30 min, 3/3 semanas
• Continuar até no máximo 16 ciclos, progressão ou toxicidade proibitiva
• Toxicidades: hematológica e neuropatia periférica
Brentuximabe vedotin (SGN35)
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www.nccn.org
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www.nccn.org
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www.nccn.org