Caso clínico
Linfoma T periférico
Clinical case
•
57-year-old, male. The clinical picture began 1 year ago, initially with generalized
arthralgias. Three months later he observed right cervical lymph node enlargement.
Although serology for Rheumatoid Arthritis was negative, radiologic and MRI images
were suggestive. He received oral metothrexate for 6 months. PS=0.
•
Physical examination: Bilateral cervical lymph node enlargement (2 cm) and right
axillar lymph node 3 cm in diameter. Thoracic and abdominal CAT scans: anterior
mediastinal and pretracheal lymph node enlargement (1-2 cm). Para-aortic, splenic
hilar, hepatic hilar, celiac, common iliac and inguinal lymph node enlargement (>
diameter 3 cm).
•
Bone marrow biopsy: normal
•
LDH= normal. Hb=12 g/dl, Ht=37%, 3500 leucocytes (54% neutrophils, 26%
lymphocytes),
125 000 platelets. HIV and HCV negative.
•
Histopathology of the axillary lymph node : Peripheral T cell lymphoma, NOS
Histopathologic findings
Immunohistochemical findings
CD3
CD5
CD4
CD8
Incidence of Common Lymphoma Subtypes
% of Total Cases
Diffuse Large B-cell
Follicular Lymphoma
85%
30%
DLBCL
Marginal zone B-cell
lymphoma, MALT
Peripheral T-cell
lymphomas
CLL/SLL
7%
CLL/SLL
Mantle Cell Lymphoma
8%
MALT
25%
Follicular
Mediastinal Large Bcell Lymphoma
Anaplastic Large Cell
Lymphoma/T-null
Burkitt
Brazil (Rio de Janeiro)
20/145
13,8
Armitage, Ann Oncol 2004
Milito, JBPML, 2002
Mature T-cell lymphomas
Defined entities
PTCL-NOS
77%
International T cell lymphoma project. JCO 2008
Peripheral T-cell lymphoma, NOS
Peripheral T-cell lymphoma, NOS
Peripheral T-cell lymphoma, NOS
Ki67
Biologic and morphologic
heterogeneity suggests
the existence of more
than one lymphoma in the
PTCL-NOS category, to
be identified
Ballester et al, Oncogene, 2006
Angioimmunoblastic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Pattern 1
Hyperplastic follicles and
paracortical expansion
Pattern 2
Atrophic follicles and
paracortical expansion
Pattern 3
Classical morphology
Angioimmunoblastic T-cell lymphoma
CD21
CD10
CXCL3
CD3
CD79a + EBER
Anaplastic Large Cell Lymphoma
CD30
EMA
ALK1
Large Cell Lymphomas: Overall Survival
1.0
0.9
0.8
Anaplastic Large T-Cell
Survival
0.7
0.6
0.5
Diffuse Large B-Cell
0.4
Burkitt-like
0.3
0.2
Peripheral T-Cell
0.1
Log Rank Test: p<0.001
0.0
0
1
2
3
4
5
6
7
8
9
Years
Armitage et al, 1997
ALK-negative ALCL
Has been controversial as to whether this is
A variant of ALCL or related to PTCL, NOS
Anaplastic Large-cell Lymphoma, ALK(provisional category)
•
Morphology:
– Identical to ALK+ ALCL
– Large cells with abundant
cytoplasm, cohesive growth,
horseshoe-shaped nuclei
(“hallmark cells”)
•
Immunophenotype:
– CD30+ strong, diffuse
– No B-cell antigens (Pax5-)
– ALK-
•
Clinical:
– Adult (med 60y)
– Prognosis intermediate between
CD30
ALK+ and PTCL-NOS
CD30
Anaplastic Large Cell Lymphoma
ALK + x ALK -
• ALK + occurs in younger age group
• ALK + has improved prognosis over ALK negative
ALCL
• ALK negative ALCL shows overlap with some PTCL,
NOS, but in general shows a plateau in survival
curve, in contrast to most PTCL
• ALK negative ALCL included in WHO 2008 as entity
distinct from ALK+ or PTCL NOS (provisional)
Failure-free Survival
Savage 2008
ALCL ALK+ vs. ALCL ALK 1.0
5 y 60% vs 36%
0.9
p=0.015
Proportion
0.8
0.7
0.6
ALK +
0.5
0.4
0.3
ALK -
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Time
Diagnosis
Anaplastic large cell lymphoma, ALKAnaplastic large cell lymphoma, ALK+
CENSOR
31
45
FAIL
40
33
TOTAL
71
78
MEDIAN
1.53
10.4
Failure-free Survival
Savage 2008
ALK neg ALCL vs PTCL-U
1.0
p=0.012
0.9
Proportion
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time
Diagnosis
ALCL ALK neg
PTCL-U
CENSOR
31
72
FAIL
40
258
TOTAL
71
330a
MEDIAN
1.53
0.91
15
Adult T-cell leukaemia/lymphoma
Adult T-cell leukaemia/lymphoma
CD30
Leucemia/linfoma de célula T do adulto no Rio de Janeiro.
Correlação clínico-patológica de 10 casos.
MILITO C, MORAIS JC, LOUREIRO M,
PULCHERI W, NUCCI M, SPECTOR N
J Bras Patol, v.36, p.45 - 53, 2000.
Principais achados
–
–
–
–
–
Forma aguda (6), linfomatosa (3) e crônica (1)
Gânglio (9), medula (5) e pele (4)
Estrongiloidíase (2), escabiose (2)
HPV, pneumocistose, herpes zoster, criptococose
Malacoplaquia pulmonar
Treatment
Distribuição dos subtipos
ILSG
UFRJ
30,6%
22,1%
6,7%
6,0%
2,4%
2,4%
< 1%
7,0%
2,4%
29,7%
20,0%
5,5%
5,5%
2,8%
4,1%
6,2%
13,8%
4,1%
n=1403
LDGC
Folicular
Linfócitos peqs
Manto
Mediastinal B
Anaplásico
Burkitt
T-periférico
Anaplásico
n=145
International Lymphoma Study Group. Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918
Milito C, Morais JC, Spector N. J Bras Patol 2002
Cancer 2007;109:1146–51.
Vose J et al. International T-cell lymphoma project. J Clin Oncol 2008
Treatment of PTCL-NOS
Standard treatment
• CHOP
• Benefit of anthracyclines?
PTCL-NOS
AILT
International T cell lymphoma project. JCO 2008
Is there an R-CHOP for PTCLs?
• Alemtuzumab (anti-CD52, Campath®)
– n=24
– CR 50%, FFS < 48%
– Infectious deaths > 10%
• Denileukin-diftitox (IL-2, Ontak®)
– n=49
– CR 75%, FFS 41%
– Early discontinuation in 20/49, 7 due to adverse
events (anaphylaxis, pneumonitis, cardiac arrest,
rhabdomyolysis)
ASCT as consolidation in PTCL
• 83 patients in CR or PR after CHOP x 6
• 55 underwent ASCT (TBI+CY)
• Reasons for exclusion
– Progressive disease 24
– Patient request 2
– Treatment related mortality 1
Reimer, JCO, Jan 2009
Reimer, JCO, Jan 2009
Reimer, JCO, Jan 2009
ASCT
• Does ASCT improve results or is it only
selecting younger patients with
chemosensitive disease?
• Primary non-responders are not eligible
• Moderately better than CHOP (?)
– Selection
Phase II trial of
RIC-AlloSCT
•
•
•
•
Relapsed/refractory PTCL/AITL/ALCL
N=17 (previous ASCT=8)
Median age 41 (23-60)
Median FUP 28 months
Corradini, JCO 2004
Allo-SCT
• French registry
• Retrospective study
• 77 pts submitted to Allo-ASCT
–
–
–
–
PTCL-NOS=27
ALCL=27
AILT=11
Age 16-58
LeGouill S et al
63%
5-year overall survival
Transplant-related mortality
Drugs being studied for PTCL
• Inibidores de HiDAC
– Vorinostat (Zolinza®) e romidepsin (Istodax®)
• Análogos de purinas
– Fludarabina, cladribina e pentostatina
– Gemcitabina, forodesina e clofarabina
• Anticorpos
–
–
–
–
Alemtuzumab (CD52)
Zanolimumab (CD4)
Siplizumab (CD2)
Bevacizumab (anti-VEGF, Avastin®) – cardiotoxicidade com
CHOP
• Inibidor de proteossomo
– Bortezomibe
Howard R. New dug therapies in PTCL. 2011
N=111 pts previamente muito tratados
JCO, 2011
Angioimmunoblastic T cell
lymphoma
Pacientes idosos ou assintomáticos
• “Watch and wait” (pode involuir espontaneamente)
• Corticóides
• Interferon
• MTX em dose baixa + corticóide
• Cladribina
Blood 2008
5y OS = 30%
IPI não estratifica
This study shows that HDT and ASCT offers
the possibility of long-term disease-free
survival to patients with AITL. Early
transplantation is necessary to achieve
optimal results.
Linfoma T angioimunoblástico
Tratamentos experimentais
• Ciclosporina
• Rituximab
• Bevacizumab (anti-VEGF, Avastin®)
• Mini-allo
Linfoma anaplásico de
grandes células
ALCL
60-80%
ALK +
Mais jovens
20-40%
ALK Menos jovens
Idade mediana = 34 anos
Idade mediana = 60 anos
SG em 5 anos = 70%
SG em 5 anos = 49%
ALCL ALK +
• Localizado: 4 CHOP + IFRT
• Avançado: 6-8 CHOP
ALCL ALK • Deve ser abordado como um linfoma T
periférico
Doença recaída
• brentuximab vedotin
• FDA: “approved for the treatment of
patients with systemic anaplastic large cell
lymphoma (ALCL) after failure of at least
one prior multi-agent chemotherapy
regimen.”