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.”