disordini linfoproliferativi (II) classificazione linfomi staging system prognosi terapia
B-Cell Neoplasms I. Precursor B-cell neoplasm: a. Precursor B-lymphoblastic leukemia/lymphoma II. Mature (peripheral) B-cell neoplasms a. B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma b. B-cell prolymphocytic leukemia c. Lymphoplasmacytic lymphoma d. Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) e. Hairy cell leuekmia f. Plasma cell myeloma/plasmacytoma g. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type h. Nodal marginal zone lymphoma (+/- monocytoid B-cells) i. Follicle center lymphoma, follicular, j. Mantle cell lymphoma k. Diffuse large cell B-cell lymphoma • Mediastinal large B-cell lymphoma • Primary effusion lymphoma l. Burkitt's lymphoma/Burkitt's cell leukemia
T-Cell and Natural Killer Cell Neoplasms I. Precursor T cell neoplasm: a. Precursor T-lymphoblastic lymphoma/leukemia II. Mature (peripheral) T cell and NK-cell neoplasms a. T cell prolymphocytic leukemia b. T-cell granular lymphocytic leukemia c. Aggressive NK-Cell leukemia d. Adult T cell lymphoma/leukemia (HTLV1+) e. Extranodal NK/T-cell lymphoma, nasal type f. Enteropathy-type T-cell lymphoma g. Hepatosplenic gamma-delta T-cell lymphoma h. Subcutaneous panniculitis-like T-cell lymphoma i. Mycosis fungoides/Sézary's syndrome j. Anaplastic large cell lymphoma, T/null cell, primary cutaneous type k. Peripheral T cell lymphoma, not otherwise characterized l. Angioimmunoblastic T cell lymphoma m. Anaplastic large cell lymphoma, T/null cell, primary systemic type
NON-HODGKIN LYMPHOMAS: 1) non-Hodkin lymphomas are a diverse collection of approximately 40 entities, with different immunopathologic and cytogenetic characteristics 2) the most frequent entities are the: - Follicle Centre lymphoma (FCL) - Diffuse Large Cell lymphoma (DLCL) 3) B-cell derived are by far more frequent compared to T-cell derived (90% vs. 10%)
INCIDENZA DEI VARI TIPI DI LINFOMA NON-HODGKIN 28% 16% 6% 30% 20% B-cell DLCL FCL T-cell NHL non follicular low grade NHL Other lymphomas
Hodgkin's lymphoma (Hodgkin's Disease) a.Nodular lymphocyte predominance Hodgkin's lymphoma b.Classical Hodgkin's lymphoma • Nodular sclerosis Hodgkin's lymphoma • Lymphocyte-rich classical Hodgkin's lymphoma • Mixed cellularity Hodgkin's lymphoma • Lymphocyte depletion Hodgkin's lymphoma
Hodgkin's Disease - Classification Type Histologic Features Frequency Prognosis Nodular sclerosis Bands of fibrosis, Most frequent type, Good Lacunar cells more common in women most are stage I-II Mixed cellular Composed of many Most frequent Fair different cells in older persons, most are stage III second most frequent overall Lymphocyte predominance Mostly B-cells and few Uncommon Good Reed-Sternberg variant cells most are stage I or II Lymphocyte depletion Many Reed-Sternberg Uncommon Poor cells and variants most are stage III or IV
CARATTERIZZAZIONE RISCHIO PROGNOSTICO: biopsia linfonodale biopsia osteo-midollare tipizzazione immunofenotipica tipizzazione molecolare stadiazione della malattia
DEFINIZIONE RISCHIO PROGNOSTICO: biopsia linfonodale biopsia osteo-midollare tipizzazione immunofenotipica tipizzazione molecolare stadiazione della malattia fattori di rischio
Fattori con valore prognostico sfavorevole indipendente: performance status > 2 LDH > normale siti extranodali 2 stadio III o IV età > 60 anni No. di fattori presenti Tipo di rischio prognostico 0-1 basso (L) 2 intermedio-basso (LI) 3 intermedio-alto (HI) 4-5 alto (H)
Overall Survival in DLCL according to risk group defined by Age-Adjusted IPI (PS, stage, LDH) C R 5-yr Risk group Score Rate survival (%) (%) Low 92 83 Low-intermediate 1 78 69 High-intermediate 2 57 46 High 3 46 32
IIL prognostic system • Age (< vs. > 60 vs) • Sex (F vs M) • Extranodal sites (0-1 vs 2) • Serum LDH (normal vs elevated) • B symptoms (absent vs present) • ESR (less than 30 vs at least 30)
Federico M et al., Blood 2000, 95: 783-789 Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases
Hodgkin's lymphoma (Hodgkin's Disease) a.Nodular lymphocyte predominance Hodgkin's lymphoma b.Classical Hodgkin's lymphoma • Nodular sclerosis Hodgkin's lymphoma • Lymphocyte-rich classical Hodgkin's lymphoma • Mixed cellularity Hodgkin's lymphoma • Lymphocyte depletion Hodgkin's lymphoma
Hodgkin's Disease - Classification Type Histologic Features Frequency Prognosis Nodular sclerosis Bands of fibrosis, Most frequent type, Good Lacunar cells more common in women most are stage I-II Mixed cellular Composed of many Most frequent Fair different cells in older persons, most are stage III second most frequent overall Lymphocyte predominance Mostly B-cells and few Uncommon Good Reed-Sternberg variant cells most are stage I or II Lymphocyte depletion Many Reed-Sternberg Uncommon Poor cells and variants most are stage III or IV
Factors with independent prognostic value for survival in lymphomas of both high and low grade histology Prognostic classification Factor age >60 performance status I P I serum LDH level (New Engl J Med 1993) Ann Arbor stage extranodal involvement Performance status aa I P I serum LDH level (New Engl J Med 1993) Ann Arbor stage Age (>60) Sex (male) I I L ESR () (Blood 2000) Serum LDH level () Systemic symptoms extranodal involvement
13-gene predictor: cured gene-espression signature fatal/refractory gene-espression signature
13-gene outcome predictor: IPI-outcome predictor:
13-gene predictor: cured gene-espression signature fatal/refractory gene-espression signature
Overall Survival of advanced-stage DLCL with 3rd generation chemotherapy regimens
Overall Survival of FCL patients
Turin-group experience with the i-HDS scheme a “high-dose” approach aimed to obtain maximal tumor cytoreduction and to exploit the in vivo-purging effect operated by chemotherapy Corradini P et al, Blood 1997 Jan 15;89:724-31 Tarella C et al, Leukemia 2000 Apr 14:740-7
I-HDS SCHEME FOR HIGH-RISK FCL PATIENTS MITOX + L-PAM + PBPC autograft VP-16 2 g/sqm MTX 8 g/sqm CTX 7 g/sqm DHAP x 2 APO x 2 PBPC/BM harvest MITOX + L-PAM + PBPC autograft DEX 40 G - C S F G - C S F
results of the Torino group experience I-HDS REGIMEN IN FCL: results of the Torino group experience Leukemia 2000, 14: 740-747 CR RATE OF 79% ACCEPTABLE RATE OF EARLY AND LATE TOXICITIES A PROJECTED EFS AT 9 YEARS OF 62% AND A PROJECTED OS OF 78% 10 20 30 40 50 60 70 80 90 100 % surviving 100 90 80 70 % surviving 60 50 40 30 Event-free survival 20 Overall survival 10 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 years years
Gianni AM et al; NEJM 1997; 336: 1290-97 “HDS vs MACOP-B in aggressive B-cell NHL“
DEVELOPMENT OF MONOCLONAL ANTIBODIES MOUSE HUMAN CHIMERICAL HUMANIZED
UNLABELED CHIMERIC ANTIBODY IMMUNOTOXIN RADIOCONJUGATE
Meccanismo d’azione mAbs effetto diretto signaling apoptosi citossico (tossine o radiomarcati) effetto indiretto complemento ADCC (NK, GN) immunosensibilizzazione
Principali anticorpi monoclonali “unlabelled” ANTIGEN NAME STRUTTURA INDICAZIONI CD20 CD25 CD52 CD22 Rituximab Basiliximab Daclizumab Campath 1H Epratuzumab Chimerico umanizzato FCL,MCL,HCL, DLCL Trapianto LLC, Trapianto FCL
Radiation-induced cytolysis RADIOIMMUNOCONJUGATE Effector mechanisms Radiation-induced cytolysis TARGET ANTIGENS: NOT SHED NOT INTERNALIZED ? NB. Properties of each immunoconiugate depend on which isotope is chosen
RITUXIMAB C-HDS + Rituximab schedule hd-CY hd- Ara-C VP16 + CDDP PBSC autografting A P O PBSC harvest PBSC harvest G-CSF G-CSF G-CSF RITUXIMAB
C-HDS + Rituximab in high-risk DLCL patients: a multicenter italian study CR OS R- HDS 82% 71 % (3yr.) historical 46-57% 32-46% (5yr.)
identification of residual disease The role of 67Ga scanning or FDG-PET in discriminating between active or fibrotic residual masses is well established
identification of residual disease The value of molecular biology techniques (PCR) in evaluating the minimal residual disease in patients with Bone Marrow involvement at presentation
DFS comparison between PCR-positive and PCR-negative patients 40 100 P<0.005 PCR negative PCR positive % surviving 80 60 20 2 10 12 years 4 6 8
IMMUNOTERAPIA NEI DISORDINI LINFOPROLIFERATIVI percentuale di guarigione ancora insufficiente crescita abbastanza lenta markers tumore-specifici o lineage-specifici chemioterapia efficace ma non eradicante monitoraggio della malattia minima residua (MMR) MMR spesso MDR+ immunosensibilita’ della MMR modelli animali disponibili
Bendandi et al., Nat Med 5: 1171-1177, 1999
Protein-based vaccine week 2 6 10 14 24 28 Id/KLH (0.5 mg + 0.5 mg) GM-CSF (150 µg/sqm) VACCINATION SCHEDULE 15 MM in first remission after HDS and PBPC infusion;
tumor burden remission phase time diagnosis relapse remission threshold remission phase time diagnosis relapse
Early detection of recurrent disease 1. The efficacy of “salvage treatment” is well known in both high and low-grade lymphomas
Early detection of recurrent disease 2. “salvage treatments” are more effective if the recurrent disease is not extensively spread
Ann Arbor stage at relapse SURVIVAL by Ann Arbor stage at relapse 100 75 p<0.0001 % 50 I-II (n=153) 25 III-IV (n=259) 5 10 I . I . L . 1999 Years after relapse