I linfomi non Hodgkin dell adolescente/giovane adulto: confronto fra trattamenti Dalla parte dell adulto 1
Incidenza (TSE/100000 abitanti) della patologia oncologica nella fascia di età 0-39 anni in Italia (registri-tumori, agg.to 2007) 2
Incidenza dei Linfomi non-hodgkin nella fascia di età 0-39 anni in Italia (registri-tumori, agg.to 2007) 3
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Incidenza dei Linfomi non-hodgkin in Italia per anno e fascia di età (registri-tumori, agg.to 2007) 5
Incidenza dei Linfomi non Hodgkin nella fascia di età 0-39 anni in Italia e Ferrara, maschi (registri-tumori, agg.to 2007) 6
Incidenza dei Linfomi non Hodgkin nella fascia di età 0-39 anni in Italia e Ferrara, femmine (registri-tumori, agg.to 2007) 7
Sopravvivenza dei Linfomi non-hodgkin in Italia per fascia di età e sesso (registri-tumori, agg.to 2004) 8
Annual Rates for new diagnoses of NHL in US adults and elderly young adults 10.5-116.4/100000 1.8-7.2/100000 Burkitt Lymphoma children 0.5-1.2/100000 Diffuse Large B-cell Lymphoma Primary mediastinal B-cell Lymphoma Anaplastic large cell lymphoma- ALK+ Years of age Modified from 9
Burkitt Lymphoma (BL) Mib1 CD20 BCL6 Courtesy of Prof. L.Cavazzini, Anatomia Patologica, Ferrara 10
Burkitt lymphoma treatment is based on Hyper-CVAD + R regimen standard intrathecal Chemotherapy consisted of 8 alternating courses every 21 days, or earlier if count recovery occurred (at least 14 days apart), without maintenance therapy. Rituximab is given during Courses 1 to 4. Odd courses (1,3,5,7) were hyper-cvad hyper-fractionated cyclophosphamide 300 mg/m2 intravenously (i.v.) every 12 hours for 6 doses Days 1 to 3 with sodium mercaptoethanesulfonate 600 mg/m2 daily via continuous infusion Days 1-3; 2) vincristine 2 mg i.v. Days 4 and 11; doxorubicin 50 mg/m2 i.v. over 24 hours via central venous catheter Day 4; and dexamethasone 40 mg daily Days 1 to 4 and 11 to 14. Even courses (2,4,6,8) were MTX and ara-c as follows: MTX 1 g/m2 i.v. over 24 hours Day 1 and ara-c 3 g/m2 i.v. every 12 hours for 4 doses 11
Burkitt lymphoma treatment is based on Hyper-CVAD + R regimen (A) Overall, event-free and disease-free survival (DFS) in BL or B-ALL after hyper-cvad plus rituximab; (B) Survival by time period for BL or B-ALL after treatment with hyper-cvad and rituximab or hyper-cvad. 12
Burkitt lymphoma treatment is based on Hyper-CVAD + R regimen 13
OTHER REGIMENS FOR BURKITT LYMPHOMA CALGB 10002 regimen (cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, leucovorin, vincristine, dexamethasone, and either doxorubicin or etoposide or cytarabine; or intrathecal triple therapy [methotrexate, cytarabine, and hydrocortisone]) + rituximab. CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) ± rituximab (3 cycles) Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with one additional cycle beyond CR) (regimen includes intrathecal methotrexate) Version 2.2013, 09/06/13 National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. 14
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Diffuse Large B-cell Lymphoma (DLBCL) BCL6 CD20 CD30 Courtesy of Prof. L.Cavazzini, Anatomia Patologica, Ferrara 16
DLBCL is best treated with R-CHOP regimen Plus: 375 mg/m2 rituximab (MabTheraTM, Hoff mann-la Roche, Basel, Switzerland) given intravenously on days 1, 22, 43, 64, 85, and 106 of the chemotherapy regimen. 17
DLBCL is best treated with R-CHOP regimen 18
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Genomic profiling of Burkitt and DLBCL in children and adult BURKITT LYMPHOMA Pediatric DLBCL adult DLBCL High proliferation rate Increased MYC expression Increased GC phenotype Increased incidence of ABC phenotype Increased additional t(14;18) Inflammation pathway Altered T- and B- cell signaling pathway Pediatric BL Inflammation pathway MYC target genes adult BL Apoptosis pathway BCR signaling GC markers BC2 family, Akt pathway, Ras Pathway IL-10 pathway The predominance of a GCB subgroup in pediatric DLBCL may partly explain the better prognosis. 20
Primary medistinal B-cell Lymphoma Primary medistinal B-cell Lymphoma is a recognized WHO entity which shows overlapping features with Mediastinal Grey Zone Lymphoma, another very rare entity of DLBCL. Both may need a differential diagnosis with Hodgkin s Lymphoma Mediastinal Grey Zone Lymphoma, is extremely rare in children and shows a dismal prognosis in adult. DLBCL MGZL PMBCL The childhood primary mediastinal large B-cell lymphomas showed a similar pattern of histology, immunophenotype and gains at 9p (59%) and 2p (41%) as adult case. chl Treatment is usually based on R-CHOP regimens 21
Primary Mediastinal B-Cell Lymphoma CD30 CD20 CD23 Courtesy of Prof. L.Cavazzini, Anatomia Patologica, Ferrara 22
Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. 23
Primary medistinal B-cell Lymphoma and dose adjusted EPOCH-R 24
Anaplastic Large Cell Lymphoma (ALCL) - ALK+ ALK ALK+ ALCL shows a broad morphologic spectrum, but all cases contain a variable proportion of cells with eccentric, horseshoe- or kidney-shaped nuclei often with an eosinophilic region near the nucleus (hallmark cells). CD30 Mib1 Courtesy of Prof. L.Cavazzini, Anatomia Patologica, Ferrara 25
Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) No particular risk factor has been clearly identified for ALCL. ALK+ ALCL occurs in young subjects (median age 35 years), with male predominance, and frequently presents at an advanced stage, with systemic symptoms and extranodal involvement. Near 40% of patients are low risk according to the International Prognostic Index (IPI). Overall, the prognosis of ALK+ ALCL is remarkably better than other T- cell lymphomas. The IPI and the PIT scores in general predict survival in patients with ALK+ ALCL. Standard first-line treatment for ALK+ ALCL consists of doxorubicincontaining polychemotherapy, which is associated with an overall response rate of 90%, a 5-year relapse-free survival of 60%, and a 5- year overall survival of 70%. 26
Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) ALCL-ALK+ is an aggressive CD30-positive T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene and the expression of ALK protein. jlhuret@atlasgeneticsoncology.org. 27
EFFETTI DELLA FUSIONE NPM-ALK SULLA FISIOLOGIA CELLULARE RESISTENZA ALL APOPTOSI, SOPRAVVIVENZA Modificato da PROLIFERAZIONE, TRASFORMAZIONE 28
Brentuximab Vedotin in relapsed ALCL - ALK+ 29
CONCLUSIONI I Linfomi non Hodgkin nel giovane adulto rappresentano una patologia potenzialmente curabile Le caratteristiche genomiche di queste malattie sono diverse da quelle del bambino I regimi polichemioterapici per il linfoma di Burkitt sono ispirati a quelli iperfrazionati utilizzati nel bambino Il ciclo CHOP e le sue varianti, unitamente alla immunoterapia con anticorpo monoclonale anti CD20 nelle forme B-cellulari, rappresenta lo scheletro del trattamento dei linfomi a grandi cellule dell adulto Potenziali nuovi bersagli per terapie biologiche sono in fase di sperimentazione clinica 30
GRAZIE PER L ATTENZIONE Francesco Cavazzini Sezione di Ematologia Università degli studi di Ferrara, cvzfnc@unife.it 9 dec 2012, 54 Annual Meeting of the American Society of Hematology, Atlanta, GA 31