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

CD3 CD4

CD5 CD8

Immunohistochemical findings

% of Total Cases Diffuse Large B-cell

Follicular Lymphoma

Marginal zone B-celllymphoma, MALT Peripheral T-celllymphomasCLL/SLL

Mantle Cell Lymphoma

Mediastinal Large B-cell LymphomaAnaplastic Large CellLymphoma/T-nullBurkitt

Incidence of Common Lymphoma Subtypes

30% DLBCL

25% Follicular 8%

MALT

7% CLL/SLL

85%

Brazil (Rio de Janeiro) 20/145 13,8

Armitage, Ann Oncol 2004

Milito, JBPML, 2002

PTCL-NOS

Mature T-cell lymphomas

Defined entities

International T cell lymphoma project. JCO 2008

77%

Peripheral T-cell lymphoma, NOS

Peripheral T-cell lymphoma, NOS

Ki67

Peripheral T-cell lymphoma, NOS

Ballester et al, Oncogene, 2006

Biologic and morphologic heterogeneity suggests the existence of more

than one lymphoma in the PTCL-NOS category, to

be identified

Angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma

Pattern 1 Hyperplastic follicles and

paracortical expansion

Pattern 3 Classical morphology

Pattern 2

Atrophic follicles and paracortical expansion

Angioimmunoblastic T-cell lymphoma

CD21 CD3

CXCL3 CD79a + EBER CD10

CD30

EMA

ALK1

Anaplastic Large Cell Lymphoma

Log Rank Test: p<0.001

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Years 0 1 2 3 4 5 6 7 8 9

Large Cell Lymphomas: Overall Survival Su

rviv

al

Anaplastic Large T-Cell

Diffuse Large B-Cell

Burkitt-like

Peripheral T-Cell

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

ALK+ and PTCL-NOS

CD30

CD30

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)

Anaplastic Large Cell Lymphoma

Diagnosis CENSOR FAIL TOTAL MEDIAN

Anaplastic large cell lymphoma, ALK- 31 40 71 1.53 Anaplastic large cell lymphoma, ALK+ 45 33 78 10.4

p=0.015

Failure-free Survival Pr

opor

tion

0.0

0.1

0.2

0.3 0.4

0.5

0.6

0.7

0.8

0.9 1.0

Time 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

ALCL ALK+ vs. ALCL ALK -

5 y 60% vs 36%

ALK -

ALK +

Savage 2008

Diagnosis CENSOR FAIL TOTAL MEDIAN ALCL ALK neg 31 40 71 1.53

PTCL-U 72 258 330a 0.91

p=0.012

Failure-free Survival ALK neg ALCL vs PTCL-U

Prop

ortio

n

0.0

0.1

0.2

0.3 0.4

0.5

0.6

0.7

0.8

0.9 1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time

Savage 2008

Adult T-cell leukaemia/lymphoma

CD30

Adult T-cell leukaemia/lymphoma

Leucemia/linfoma de célula T do adulto no Rio de Janeiro. Correlação clínico-patológica de 10 casos.

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

MILITO C, MORAIS JC, LOUREIRO M, PULCHERI W, NUCCI M, SPECTOR N

Treatment

Distribuição dos subtipos

ILSG UFRJ n=1403 n=145

LDGC 30,6% 29,7% Folicular 22,1% 20,0% Linfócitos peqs 6,7% 5,5% Manto 6,0% 5,5% Mediastinal B 2,4% 2,8% Anaplásico 2,4% 4,1% Burkitt < 1% 6,2% T-periférico 7,0% 13,8% Anaplásico 2,4% 4,1%

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?

International T cell lymphoma project. JCO 2008

PTCL-NOS AILT

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

• French registry • Retrospective study • 77 pts submitted to Allo-ASCT

– PTCL-NOS=27 – ALCL=27 – AILT=11 – Age 16-58

Allo-SCT

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

JCO, 2011

N=111 pts previamente muito tratados

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.

• Ciclosporina • Rituximab • Bevacizumab (anti-VEGF, Avastin®)

• Mini-allo

Linfoma T angioimunoblástico Tratamentos experimentais

Linfoma anaplásico de grandes células

ALCL

ALK + ALK -

60-80% 20-40%

Mais jovens Idade mediana = 34 anos

SG em 5 anos = 70% SG em 5 anos = 49%

Menos jovens Idade mediana = 60 anos

ALCL ALK +

• Localizado: 4 CHOP + IFRT

• Avançado: 6-8 CHOP

• Deve ser abordado como um linfoma T

periférico

ALCL ALK -

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.”