BASSO GRADO A piccoli linfociti B follicolare, prevalentemenete a piccole cellule clivate C follicolare misto, piccole cellule clivate e grandi cellule GRADO INTERMEDIO D follicolare, prevalenza di grandi cellule E diffuso, a piccole cellule clivate F diffuso, misto a piccole e grandi cellule G diffuso a grandi cellule ALTO GRADO H immunoblastico I linfoblastico J piccole cellule non clivate (burkitt) Table 1. International Lymphoma Study Group Classification B-Cell Lymphoma T/NK-Cell Lymphoma Precursor B-lymphoblastic Small lymphocytic (CLL) Lymphoplasmacytic Mantle cell Follicle center, follicular Grade 1* Grade 2* Grade 3* Follicle center diffuse, small cell Marginal zone B-cell, MALT type Marginal zone B-cell, nodal Marginal zone B-cell, splenic Hairy cell leukemia Plasmacytoma Diffuse large B-cell Diffuse mediastinal large B-cell Burkitt’s High grade B-cell, Burkitt-like Unclassifiable low grade Unclassifiable high grade Precursor T-lymphoblastic T-cell chronic lymphocytic leukemia Large granular lymphocyte leukemia Mycosis fungoides Peripheral T cell, unspecified Medium-sized Mixed medium and large cell Large cell Lymphoepithelioid Hepatosplenic Subcutaneous panniculitic Angioimmunoblastic Angiocentric, nasal Intestinal Adult T-cell lymphoma/leukemia Anaplastic large cell (including null phenotype) Anaplastic large cell, Hodgkin’s-like Unclassifiable low grade Unclassifiable high grade Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918 International Prognostic Index (I.P.I.) Fattore assente presente stadio LDH performance status I-II normali 0-1 III-IV elevate 2o> Categoria - rischio basso int. basso int. alto alto 0 1 2 3 RC OS 5 anni 92% 78% 57% 46% 83% 69% 46% 32% Shipp et al., NEJM 329, 387-394. 1993 Shipp N Engl J Med 329, 987, 1993 OS and IPI Age adjusted index, patients < 69 (n = 1274) 100 90 80 70 60 50 40 30 20 10 0 12 24 L 28-2-99 Li Hi 36 H 48 60 noi OS dal trapianto SONO TROPPPO BASSE Shipp N Engl J Med 329, 987, 1993 OS and IPI Age adjusted index, patients < 69 (n = 1274) 100 90 80 70 60 50 40 30 20 10 0 24 36 48 BASSE 60 SONO TROPPPO 12 28-2-99 L Li Hi H noi OS dal trapianto Linfomi - EFS dalla diagnosi 39 patients with no or 1 risk factors I.P.I. 120 100 79% BEAM (n=23) 80 MACOP-B (n=16) 60 75% 40 20 p = 0.82679 0 0 1 2 3 4 5 MACOP-B 6 7 8 BEAM Cortelazzo Br J Haematol 99, 379, 1997 9 10 Linfomi - EFS dalla diagnosi 120 100 BEAM (n=61) 80 65% 60 41% 40 MACOP-B (n=60) 20 p = 0.0281 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 MACOP-B BEAM Cortelazzo Br J Haematol 99, 379, 1997 Fisher EFS Fisher RI, et al. New Engl J Med 328, 1002, 1993 Overall survival Fisher RI, et al. New Engl J Med 328, 1002, 1993 CHOP vs three intensive chemotherapy regimens for advanced NHL La sopravvivenza globale e la sopravvivenza libera da eventi non sono risultati significativamente differenti La incidenza di gravi manifestazioni tossiche e il costo del CHOP sono inferiori il CHOP rimane il miglior trattamento oggi disponibile per pazienti con LNH in stadio avanzato a grado di malignità medio/ alto Fisher N Engl J Med 328, 1002, 1993 Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 Poiche la quota di pazienti guariti dalla chemioterapia convenzionale è <50%, sono giustificati approcci terapeutici sperimentali per migliorare la nostra possibilità di curare la malattia se un paziente non è elegibile o non vuole partecipare ad uno studio clinico, il CHOP per quanto inadeguato possa essere rimane il "gold standard" Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 Quali approcci sperimentali? 1) aumentare la dose intensity dei farmaci usati nei protocolli standard 2) trapianto autologo di midollo osseo o di cellule staminali periferiche dopo terapia mieloablativa 3) (ndr) nuovi farmaci Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Fisher R.I. et al. 3 years est. O.S. DFS toxic deaths ProMACe-C ytaBOM 50% 46% 3% MACOP-B 50% 41% 6% m-BACOD 52% 46% 5% CHOP 54% 41% 1% N Engl J Med 328, 1002, 1993 Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 6 years est. O.S. PFS ProMACe-CytaB OM 46% 34% MACOP-B 41% 32% m-BACOD 40% 36% CHOP 42% 33% Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 6 years est. O.S. PFS ProMACe-CytaB OM 46% 34% MACOP-B 41% 32% m-BACOD 40% 36% CHOP 42% 33% Gianni Gianni A.M. et al. N Engl J Med 336, 1290, 1997 MACOP-B HDS-CHT RC 70% 96% P=0.001 FFP 49% 84% P<0.001 FFR 70% 88% P=0.055 EFS 49% 76% P=0.004 OS 7 years 55% 81% P=0.09 Linfomi - EFS dalla diagnosi 100 76% 80 60 40 49% 20 p = 0.004 0 0 1 2 3 4 5 6 MACOP-B Gianni et al, N Engl J Med 336, 1290, 1997 7 HDS Linfomi - EFS dalla diagnosi 100 76% 80 60 40 49% 20 p = 0.004 0 0 1 2 3 4 5 6 MACOP-B Gianni et al, N Engl J Med 336, 1290, 1997 7 HDS HD-CHT vs MACOP-B in aggressive B-cell NHL at diagnosis High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type Gianni N Engl J Med 336, 1290, 1997 De vita, NEJM review Hodgkin Philip Philip T. et al. New Engl J Med 333, 1540, 1995 Philip T. et al. New Engl J Med 333, 1540, 1995 Haioun Survival benefit of High-Dose Therapy in Poor-Risk Aggressive Non-Hodgkin’s Lymphoma: Final Analysis of the Prospective LNH87-2 Protocol A Groupe d’Etude des Lymphomes de l’Adulte Study Haioun C, Lepage E, Gisselbrecht C et al. J Clin Oncol 18, 3025, 2000 LNH87-2 median follow-up of 8 years final analysis: randomized study - consolidative sequential CHT (ifosfamide, etoposide, asparaginase, and cytarabine) vs - HDT using cyclophosphamide, carmustine, and etoposide (CBV regimen) followed by stem-ceIl transplantation Haioun C., et al. J Clin Oncol 18, 3025, 2000 in patients with • aggressive NHL • in first complete remission after induction • higk/intermediate and high-risk patients identified by the age-ad justed internationai prognostic index. Haioun C., et al. J Clin Oncol 18, 3025, 2000 916 eligible patients 451 with two or three risk factors. 277 (61%) reached complete remission 236 randomized 125 patients HDT 111 sequential CHT Haioun C., et al. J Clin Oncol 18, 3025, 2000 8 year OS ABMT 64% (95% CI 55%-73%) CHT 49% (95% CI 39%-59%) Haioun C., et al. J Clin Oncol 18, 3025, 2000 8 year DFS ABMT 55% (95% CI 46%-64%) CHT 39% (95% CI 30%-48%) ABMT CHT Haioun C., et al. J Clin Oncol 18, 3025, 2000 Conclusion: On the basis of the final analysis of this prospectively treated series of patients, retrospectively analyzed on the basis of the International Prognostic Index, we hypotesize that HDT benefits patients at higher risk who achieve complete remission after induction treatment Haioun C., et al. J Clin Oncol 18, 3025, 2000 T - cell Peripheral T-CeII Lymphoma - JAMES O. ARMITAGE: MD, JOHN P GREER. MD.t ALEXANDRA M. LEViNE. MDDENNIS D. WEISENBURGER. MD.§ SILVIA C. FORMENTI, MD.* MAWT1N BAST. BS, SUE CONLEY, BA.’ JENE PIERSON. BS, JAMES UNDER. MD,§ JOHN B. COUSAR. MD AND BHARAT N. NATHWANI, MD Cancer 63:158-163, 1989. Clinical data were reviewed from 134 cases of peripheral T-cell lymphoma diagnosed in three centers. The median age of the patients was 57 years (range, 4-97 yasrs), 59% were male, and 36 patients (27%) had a history of a preceeding disorder of the immune system. The tumors were grooped histologically into large cell (43%), mixed large and small cell (40%), sud small cell (17%). The stage at diagnosis was I(7%), II (21%), III (22%), and IV (50%). B symptoms were present in 57%. The most frequent sites of extranodal involvement were bone marrow (35%), skin (13%), and lung (11%). Eighty patients were treated with a multiagent chemotherapy regimen with proven curative potential in aggressive non-Hodgkin’s lymphomas and the remainder of the patients received less intensive chemotherapy (36 patients), radiotherapy (9 patients), or no treatment (9 patients). Fifty percent of the Intensively treated patients achieved complete remission and the actuarial 4-years survival was 45%. However, the 4-year disease free survival in patients with Stage IV disease was only 10%. Although peripheral T-cell lymphomas appeared similar in many ways to their B-cell counterpart, disease-free survival by stage was low and patients with Stage IV disease Armitage, Cancer 63:158-163, 1989. Table 3. Distribution of NHL Cases by the Consensus Diagnosis % Diffuse large B-cell 422 30.6 Follicular 304 22.1 Marginal zone B-cell, MALT 105 7.6 Peripheral T-cell 96 7.0 Small B-lymphocytic (CLL) 93 6.7 Mantle cell 83 6.0 Primary mediastinal large B-cell 33 2.4 Anaplastic large T/null-cell 33 2.4 High grade B-cell, Burkitt-like 29 2.1 Marginal zone B-cell, nodal 25 1.8 Precursor T-lymphoblastic 23 1.7 Lymphoplasmacytoid 16 1.2 Marginal zone B-cell, splenic 11 Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918 < Table 6. Patient Characteristics by Histologic Type 5-yr Diagnosis FFS Follicular, all grades % Median %Stage % Marr % PI % PI % 5-yr Male Age 1 or 2 Pos 0/1 4/5 OAS 42 59 33 42 39 6 72 27 11 74 60 57 51 59 46 29 25 25 41 50 44 47 26 48 44 43 24 25 18 77 58 40 Mantle cell 74 63 19 63 19 19 Marginal zone B-cell, MALT 45 61 66 14 38 5 Marginal zone B-cell, nodal 41 58 18 41 36 9 Small lymphocytic 53 65 6 73 17 10 Lymphoplasmacytoid 53 63 20 73 20 13 Diffuse large B-cell 55 64 51 17 31 16 Primary mediastinal large B-cell 34 37 66 3 44 9 Burkitt’s 89 31 56 33 44 22 Burkitt-like 59 55 50 21 25 18 T-lymphoblastic 74 25 13 43 35 22 Peripheral T-cell, all types 56 61 18 37 14 27 Anaplastic large T/ Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918 null-cell 69 33 50 12 50 19 % Table 7. Survival by Histologic Type and the International Prognostic Index immunologic data. For other types, such as the lymphoplas-macytoid, nodal marginal zone B-cell, and high-grade B-cell % 5-yr OAS % 5-yr FFS Burkitt-like lymphomas, imprecise histologic criteria and the Index Index Index Index lack of specific immunologic markers led to a diagnostic Consensus Diagnosis 0/1 4/5 0/1 4/5 accuracy of only 53% to 65%. Further definition of these Follicular, all grades 84 17 55 6 entities is clearly needed. Because the need for immunophe- Mantle cell 57 0 27 0 notyping cannot be predicted before biopsy, it is vital that Marginal zone B-cell, MALT 89 40 83 0 each patient have tissue available for immunophenotyping Marginal zone B-cell, nodal 76 50 30 0 and other special studies to facilitate proper patient care. In Small lymphocytic (CLL) 76 38 35 13 many cases, this will require communication between the Diffuse large B-cell 73 22 63 19 oncologist, the surgeon, and the pathologist. Primary mediastinal large B-cell 77 0 69 0 The 13 major types of NHL shown in Fig 1 made up over High grade B-cell, Burkitt-like 71 0 71 0 Precursor T-lymphoblastic 29 40 29 40 90% of the cases in our study, with diffuse large B-cell Peripheral T-cell, all types 36 15 27 10 lymphoma and follicular lymphoma comprising over 50% Blood, Voland 89, the No newly 11 (June 1), 1997: pp 3909 Anaplastic large T/null-cell 81 83 49 83 of the cases recognized Linfomi Event Free Survival 100 80 60 40 20 0 0 1 2 3 CHOP - Verdonck MACOP-B Fisher 4 5 6 MACOP-B Gianni 7 8 9 MACOP-B Cortelazzo Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena gennaio 1998 10 Linfomi Event Free Survival 110 HD-CHT 100 90 80 70 60 50 CHT 40 0 1 2 3 4 5 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena 6 gennaio 1998 7 Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 Poiche la quota di pazienti guariti dalla chemioterapia convenzionale è <50%, sono giustificati approcci terapeutici sperimentali per migliorare la nostra possibilità di curare la malattia se un paziente non è elegibile o non vuole partecipare ad uno studio clinico, il CHOP per quanto inadeguato possa essere rimane il "gold standard" MACOP-B vs ProMACE-MOPP in the treatment of advanced diffuse NHL: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. ProMACE-MOPP MACOP-B CR 3-year OS 3-yearPFS 49.1% 45.2% 36.4% 52.3% 52.3% 36.1% CONCLUSION: No significant differences in terms of efficacy and/or toxicity between ProMACE-MOPP and MACOP-B are evident. These results are consistent with recent randomized showing that1994 the 12(7): newSertoli-MR; trials et-al J-Clin-Oncol. Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 Quali approcci sperimentali? 1) aumentare la dose intensity dei farmaci usati nei protocolli standard 2) trapianto autologo di midollo osseo o di cellule staminali periferiche dopo terapia mieloablativa 3) (ndr) nuovi farmaci NHL: CHT sensitive relapse PARMA protocol 215 pats at relapse DHAP x 1 BM harvesting DHAP x 1 Responders (109) N.R. out DHAP x 4 Philip N Engl J Med 333, 1540, 1995 ABMT NHL: CHT sensitive relapse Follow up median 63 months ABMT DHAP number 49 37 toxic deaths 4/49 (8,2% ) 0 RC+RP 84% 44% 5 years EFS 46% 12% p = 0.001 5 years OS 53% 32% p = 0.038 Philip N Engl J Med 333, 1540, 1995 ABMT vs CHT in relapsed CHT sensitive NHL Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globale Per il futuro dovremmo condurre studi che consentano di stabilire se la tossicità può essere ridotta dall'impiego di cellule staminali periferiche e di fattori di crescita Philip N Engl J Med 333, 1540, 1995 HD-CHT in poor prognosis NHL at diagnosis Two years actuarial estimates STANDARD INTENSIVE EFS 35% 61% p = 0.01 OS 35% 64% p = 0.01 Pettengell J Clin Oncol 14, 586, 1996 HD-CHT in poor prognosis NHL at diagnosis pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiore la differenza giustifica un confronto formale nell'ambito di uno studio randomizzato Pettengell J Clin Oncol 14, 586, 1996 Gianni A.M. et al. N Engl J Med 336, 1290, 1997 MACOP-B HDS-CHT RC 70% 96% P=0.001 FFP 49% 84% P<0.001 FFR 70% 88% P=0.055 EFS 49% 76% P=0.004 OS 7 years 55% 81% P=0.09 Linfomi - EFS dalla diagnosi 100 76% 80 60 40 49% 20 p = 0.004 0 0 1 2 3 4 5 6 MACOP-B Gianni et al, N Engl J Med 336, 1290, 1997 7 HDS HD-CHT vs MACOP-B in aggressive B-cell NHL at diagnosis High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type Gianni N Engl J Med 336, 1290, 1997 Linfomi - EFS dalla diagnosi 120 100 BEAM (n=61) 80 65% 60 41% 40 MACOP-B (n=60) 20 p = 0.0281 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 MACOP-B BEAM Cortelazzo Br J Haematol 99, 379, 1997 NHL: CHT sensitive relapse Follow up median 63 months ABMT DHAP number 49 37 toxic deaths 4/49 (8,2% ) 0 RC+RP 84% 44% 5 years EFS 46% 12% p = 0.001 5 years OS 53% 32% p = 0.038 Philip N Engl J Med 333, 1540, 1995 ABMT vs CHT in relapsed CHT sensitive NHL Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globale Per il futuro dovremmo condurre studi che consentano di stabilire se la tossicità può essere ridotta dall'impiego di cellule staminali periferiche e di fattori di crescita Philip N Engl J Med 333, 1540, 1995 HD-CHT in poor prognosis NHL at diagnosis Two years actuarial estimates STANDARD INTENSIVE EFS 35% 61% p = 0.01 OS 35% 64% p = 0.01 Pettengell J Clin Oncol 14, 586, 1996 HD-CHT in poor prognosis NHL at diagnosis pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiore la differenza giustifica un confronto formale nell'ambito di uno studio randomizzato Pettengell J Clin Oncol 14, 586, 1996 Linfomi - EFS dalla diagnosi 120 100 BEAM (n=61) 80 65% 60 41% 40 MACOP-B (n=60) 20 p = 0.0281 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 MACOP-B BEAM Cortelazzo Br J Haematol 99, 379, 1997 NHL: CHT sensitive relapse Follow up median 63 months ABMT DHAP number 49 37 toxic deaths 4/49 (8,2% ) 0 RC+RP 84% 44% 5 years EFS 46% 12% p = 0.001 5 years OS 53% 32% p = 0.038 Philip N Engl J Med 333, 1540, 1995 ABMT vs CHT in relapsed CHT sensitive NHL Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globale Per il futuro dovremmo condurre studi che consentano di stabilire se la tossicità può essere ridotta dall'impiego di cellule staminali periferiche e di fattori di crescita Philip N Engl J Med 333, 1540, 1995 HD-CHT in poor prognosis NHL at diagnosis Two years actuarial estimates STANDARD INTENSIVE EFS 35% 61% p = 0.01 OS 35% 64% p = 0.01 Pettengell J Clin Oncol 14, 586, 1996 HD-CHT in poor prognosis NHL at diagnosis pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiore la differenza giustifica un confronto formale nell'ambito di uno studio randomizzato Pettengell J Clin Oncol 14, 586, 1996 Linfomi - EFS dalla diagnosi 120 100 BEAM (n=61) 80 65% 60 41% 40 MACOP-B (n=60) 20 p = 0.0281 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 MACOP-B BEAM Cortelazzo Br J Haematol 99, 379, 1997 Follicular low grade lymphoma Patients No 5 years survival median overall survival sex age Stage B symptoms 91 66% 111 months 5 years survival male 57% female 73% < 70 67% > 70 28% I or II III or IV 57% yes 41% no 69% Morel et al., Ann Hematol 66, 303, 1993 0.03 0.004 89% 0.06 0.03 Intermediate/ high-grade lymphomas response rate treatment No O.R. C.R CHOP m-BACOD Pro-MACE-CytaBOM MACOP-B 225 223 233 218 80% 82% 87% 83% 44% 48% 56% 51% Fisher et al, NEJM 328, 1002, 1993 Intermediate/ high-grade lymphomas response rate treatment No O.R. C.R CHOP m-BACOD Pro-MACE-CytaBOM MACOP-B 225 223 233 218 80% 82% 87% 83% 44% 48% 56% 51% Fisher et al, NEJM 328, 1002, 1993 Intermediate/ high-grade lymphomas 3 years overall survival treatment No CHOP m-BACOD Pro-MACE-CytaBOM MACOP-B 225 223 233 218 Fisher et al, NEJM 328, 1002, 1993 54% 52% 50% 50% P=0.9 Intermediate/ high-grade lymphomas 3 years overall survival treatment No CHOP m-BACOD Pro-MACE-CytaBOM MACOP-B 225 223 233 218 Fisher et al, NEJM 328, 1002, 1993 54% 52% 50% 50% P=0.9 Intermediate/ high-grade lymphomas 3 years D.F.S. treatment No CHOP m-BACOD Pro-MACE-CytaBOM MACOP-B 225 223 233 218 Fisher et al, NEJM 328, 1002, 1993 41% 46% 46% 41% P=0.35 Intermediate/ high-grade lymphomas 3 years D.F.S. treatment No CHOP m-BACOD Pro-MACE-CytaBOM MACOP-B 225 223 233 218 Fisher et al, NEJM 328, 1002, 1993 41% 46% 46% 41% P=0.35 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998 Abstract: 575 (EBMT) Allogeneic stem cell transplantation for advanced hodgkin's disease: The M.D. Anderson experience P. Anderlini, B. Andersson, J. Gajewski, S. Giralt, R. Mehra, D. Claxton, N. Ueno, I. Khouri, D. Przepiorka, M. Donato, M. Körbling, R. Champlin M.D. Anderson Cancer Center, Houston, USA Since 1989 a total of nine allogeneic bone marrow (alloBMT) or blood stem cell transplantation (alloSCT) for relapsed/refractory Hodgkin's disease (HD) from HLA-identical related donors have been performed at MDACC. The results are as follows: Time period 1989-1996 Stem cell source AlloBMT (n = 5) Median patient age (yrs) 27 (23-41) Conditioning regimen 1996-present AlloSCT (n = 4). 30 (21-35) CBV (n = 3), Bu-Cy (n = 3), Bu-Cy (n = 2) other (n = 1) Status at transplant Prior autologous BMT Outcome Refr (n = 1) Rel 2 or 3 (n = 4) rel 2/3 (n = 2), other (n = 2) 4/5 3/4 Expired 5/5 Alive 4/4 (4 within 6 mos) (2 in remission) Median follow-up (mos) n.a. 7 (2-10) The causes of death in the alloBMT pts. were relapse (n = 1), transplant-related mortality (TRM) (n = 3) and unknown (n = 1). Conclusions: (1) As reported in the literature (mainly from registry data), alloBMT in relapsed/refractory HD was associated with high TRM and relapse rates. (2) The reason for the seemingly improved early TRM and short-term outcome recently seen in allografted HD patients at MDACC is unclear. Several factors, such as better supportive care, FK506based GVHD prophylaxis and possibly the introduction of alloSCTs and IV busulfan may be responsible for this very encouraging trend. P. Anderlini, e t al. EBMT 1998 patients number 42 median age 33 (16-56) follicular large cell diffuse mixed diffuse large cell immunoblastic 6 5 21 10 stage III-IV bulky > 8 cm 37 (88%) 36 (86%) IPI High IPI HI 25 (60%) 17 (40%) Nademanee, Blood 90, 3844, 1997 standard intensive n. median age centroblastic immunoblastic T cell unclassified Ki-1 other bulky 18/33 stage IV 25/33 34 49 (19-60) 18 2 4 5 3 2 22/34 27/34 33 37 (23-60) 19 1 3 8 1 1 Pettengel J Clin Oncol 14, 586, number median age standard 60 49(19-60) intensive 61 45 (18-60) large cleaved (G) l.c. with LG component immunoblastic anaplastic 37 5 16 2 37 6 7 11 stage II stage III-IV bulky > 10cm bone marrow adverse features 0-1 adverse features 2-3 17 43 26 10 16 44 18 43 Cortelazzo 31 Br J 15 Haematol 23 99, 379, 38 1997 CHOP m-BACOD ProMACE number 218 age (median) (19-79) >65 24 225 223 233 56 (15-79) 26 57 (18-81) 25 54 (17-81) 27 57 Bulky % 40 41 41 40 Marrow % 25 26 27 27 LDH >250 % 45 43 42 43 MACOP-B CytaBOM WF group Fisher, NEJM 328, 1002, 1993 standard (50) intensive (48) age group G group H T cell 35 (17-60) 88% 12% 0 34 (18-59) 91% 10% 0 stage I-II stage III-IV 32% 68% Gianni et al, 28% NEJM 336, 72% 1290, 1997 Marrow Bulky 0 70% 0 76% IPI L-IL IPI HI-H 2% 74% 0 94% TI: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma AU: Gordon-LI; Harrington-D; Andersen-J; Colgan-J; Glick-J; Neiman-R; Mann-R; Resnick-GD; Barcos-M; Gottlieb-A; et-al AD: Northwestern University Medical School, Department of Medicine, Chicago, IL 60611. SO: N-Engl-J-Med. 1992 Nov 5; 327(19): 1342-9 AB: In 1984, the Eastern Cooperative Oncology Group began a randomized controlled clinical trial of patients with advanced (stage III or IV) diffuse mixed or diffuse largecell lymphoma to determine whether complete-remission rates, survival, and toxicity differed when patients were From July 1984 through January 1988, 392 patients were enrolled. After a median follow-up of four years, there were no significant differences in rates of complete remission, time to treatment failure, disease-free survival, or overall survival in the patients treated with CHOP as compared with those treated with m-BACOD. However, there was more severe and life-threatening pulmonary, infectious, and hematologic toxicity associated with the m-BACOD regimen. CONCLUSIONS. For patients with stage III or IV diffuse mixed or diffuse large-cell lymphoma, CHOP is superior to m-BACOD. Gordon-LI; et al. N-Engl-J-Med. 1992 Nov 5; 327(19): TI: Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group. AU: Cooper-IA; Wolf-MM; Robertson-TI; Fox-RM; Matthews-JP; Stone-JM; Ding-JC; Dart-G; Matthews-J; Firkin-FC; et-al AD: Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia. SO: J-Clin-Oncol. 1994 Apr; 12(4): 769-78 Between October 1986 and June 1991, 304 patients were randomized to compare complete response rates, time to failure, survival, and toxicity for patients with RESULTS: • There was no significant difference in complete response rates (51% for MACOP-B v 59% for CHOP), failure-free survival, or overall survival in the two treatment arms. • Toxicity was significantly more severe with MACOP-B. • CHOP remains the standard chemotherapy for this disease, against which all new regimens should be769 Cooper-IA; et al. J-Clin-Oncol. 1994 Apr; 12(4): compared. CASISTICA • Pazienti 17 – sesso • maschi 9 • femmine 8 • Età – media 39 (20-58) – mediana 41 • Stato al trapianto • RC 1 • RP • Recidiva >2 10 5 2 • Patologia • • • • • LNH MdH LLA LMA MM 11 2 2 1 1 PATOLOGIE MdH 12% LNH 64% MM 6% LA 18% TI: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. AU: Haioun-C; Lepage-E; Gisselbrecht-C; Bastion-Y; Coiffier-B; Brice-P; Bosly-A; Dupriez-B; Nouvel-C; Tilly-H; Lederlin-P; Biron-P; Briere-J; Gaulard-P; ReyesF AD: Hopital Henri Mondor, Creteil, France. SO: J-Clin-Oncol. 1997 Mar; 15(3): 1131-7 PURPOSE: To compared consolidative sequential treatment (ifosfamide, etoposide, asparaginase, and cytarabine) versus the high-dose regimen of cyclophosphamide, carmustine, and etoposide (CBV) 541 patients in complete remission were assigned to receive consolidation by either sequential chemotherapy (n = 273) or autotransplant (n = 268). In the higher risk population: 5 years estimated CBV CHT DFS OS 59% 39% P = .01 65% 52% P = .06 CONCLUSION: Dose-intensive consolidation therapy should be considered for patients at higher risk who achieve complete remission after induction treatment. Haioun-C; et al-J-Clin-Oncol. 1997 Mar; 15(3): 1131-7 TI: Single and double autotransplants for relapsing/refractory Hodgkin's disease: results of two consecutive trials. AU: Ahmed-T; Lake-DE; Beer-M; Feldman-EJ; PretiRA; Seiter-K; Helson-L; Mittelman-A; Kancherla-R; Ascensao-J; Akhtar-T; Cook-P; Goldberg-R; Coleman-M AD: Division of Oncology and Hematology, New York Medical College, Valhalla 10595, USA. SO: Bone-Marrow-Transplant. 1997 Mar; 19(5): 449-54 AB: Patients with refractory disease were offered a second transplant with different conditioning in the absence of progression or excessive toxicity. 45 refractory patients (24 with primary refractory disease and 21 with refractory relapse) received a second cycle. After the first cycle , 12 were in CR and 11 in PR and 10 The CR rate is 37% in patients with refractory relapse and 19% in those with primary refractory disease. At a median follow-up of 4 years, median survival is 45 months. Progression-free survival of the refractory patients who could receive a second cycle was similar to that of patients with sensitive disease. Conclusion •A sequential transplant strategy is feasible. •A subgroup of patients with refractory disease can achieve long-term survival after sequential BMT. Ahmed-T; et al. Bone-Marrow-Transplant. 1997 Mar; 19(5): 449- BEC-2 BCNU 400 mg/m2 day -5 VP-16 1800 mg/m2 day -5 cyclophosphamide 2500 mg /m2 days -5 and TMJ Thiotepa 250 mg/m2 days -7, -6, -5 Mitoxantrone 40 mg/m2 day -7 Carboplatin 330 mg/m2 days -7, -6, -5 Ahmed-T; et al. Bone-Marrow-Transplant. 1997 Mar; 19(5): 449- REGIME DI CONDIZIONAMENTO • • • • • BEAM CBV BuCy MTM HD L-PAM 12 1 1 2 1 RISULTATI • ATTECCHIMENTO • VIVI – in remissione – in recidiva 17/17 17/17 15/17 2/17 (100%) (100%) • T.R.M. 0/17 (0%) (12%) • Follow-up – media – mediana 5 mesi 5 mesi (1-10) Linfomi - conta CD34 - colonie - citogenetica - diagnostica molecolare diagnosi CHOP 4 cicli Cy 4gr/m2 +G-CSF PBPCs HD CHT (BEAM) - criopreservazione reinfusione NHL INTERMEDIATE/HIGH GRADE AUTOGRAFTING PFS % 100 CR 1 n = 563 80 63% 60 40 CR 2 n = 472 20 1 EBMT registry 1995 2 3 4 5 36% 6 7 8 years NHL at relapse disease free survival % 80 60 40 sensitive relapse 20 resistant relapse 1 2 3 4 5 6 7 8 years after transplantation Trapianto Autologo Perché nei linfomi? TI: Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell non-Hodgkin's lymphoma in first remission: a pilot study. AU: Freedman-AS; Takvorian-T; Neuberg-D; Mauch-P; Rabinowe-SN; Anderson-KC; SoifferRJ; Spector-N; Grossbard-M; Robertson-MJ; et-al AD: Division of Tumor Immunology, DanaFarber Cancer Institute, Boston, MA 02115. SO: J-Clin-Oncol. 1993 May; 11(5): 931-6 AB: Twenty-six patients with advanced-stage diffuse intermediate/high-grade B-cell NHL (including 16 patients with diffuse small cleavedcell [DSC]) were selected at presentation by histologic and clinical characteristics to have less than a 25% probability of long-term DFS with conventional treatment. After induction chemotherapy, 16 patients were in complete remission (CR) and 10 were in a minimal disease state. Patients were then treated with high-dose cyclophosphamide, total-body irradiation (TBI), and anti-B-cell monoclonal antibody-purged ABMT. RESULTS: • no acute in-hospital treatment deaths occurred. •The median follow-up period for the 21 patients who are alive and disease-free is 32 months. •The DFS rate is estimated to be 85% at 28 months and thereafter. CONCLUSION: This pilot study suggests that consolidation of first remission with ABMT may improve the long-term DFS rate for diffuse intermediate/high-grade NHL patients at high risk for relapse. A phase II multicenter trial of high-dose sequential chemotherapy and peripheral blood stem cell transplantation as initial therapy for patients with high-risk non-Hodgkin's lymphoma. Schenkein-DP; et al. (Tupper Research Institute, New England Medical Center, Boston, MA, USA). Biol-Blood-Marrow-Transplant. 1997 Oct; 3(4): 210-6 Thirty-two patients with high-risk NHL (defined by the age-adjusted international index) underwent HDS chemotherapy followed by PBSC transplantation. HDS consisted of Phase I (adriamycin, vincristine, and prednisone); Phase II (cyclophosphamide, filgrastim [G-CSF], and PBSC harvest); Phase III (methotrexate, leucovorin, vincristine; Phase IV (etoposide, filgrastim [G-CSF]); and Phase V (mitoxantrone, melphalan, autologous peripheral blood stem cell infusion, and filgrastim [G-CSF]). Radiation therapy was given to sites of previous bulk disease, 2400 cGy, (D + 30-100)]. Schenkein-DP; et al. Biol-Blood-Marrow-Transplant. TRM median follow-up OS at 18 months RFS at 18 months 6.25% 18.8 months (4-44) 78% (95% CI 37-90%) 67% (95% CI 46-88%) High-dose sequential chemotherapy with initial PBSC transplantation is well tolerated and appears effective in high-risk NHL. Superior results were noted in patients with intermediate grade versus those with small noncleaved or lymphoblastic NHL. Schenkein-DP; et al. Biol-Blood-Marrow-Transplant. 1997 Oct; 3(4): 210-6 TI: Autotransplantation for relapsed or refractory non-Hodgkin's lymphoma (NHL): long-term follow-up and analysis of prognostic factors. AU: Rapoport-AP; et. al. AD: Department of Medicine, University of Rochester, School of Medicine and Dentistry, NY, USA. SO: Bone-Marrow-Transplant. 1997 May; 19(9): 883-90 AB: One hundred and thirty-six patients autografted for relapsed or refractory non-Hodgkin's lymphoma (NHL) were evaluated to assess longterm event-free survival and to identify important prognostic factors. Patients were treated with 1-3 cycles o DHAP or other regimens until a complete response was obtained or there was no significant change and riceived high-dose therapy (primarily carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC)) followed by unpurged autologous stem cell rescue. Rapoport-AP; et. al. Bone-Marrow-Transplant. 1997 TRM 5-year EFS median FU years). 4.4%. 34% (95% CI 24-44%) 3 years (range 0-7.5 New strategies are needed to reduce the high rate of relapse (50-60%) following auto-transplantation for relapsed or refractory NHL. Rapoport-AP; et al. Bone-Marrow-Transplant. 1997 May; TI: Primary diffuse large B-cell lymphoma of the mediastinum: outcome following high-dose chemotherapy and autologous hematopoietic cell transplantation. AU: Sehn-LH; Antin-JH; Shulman-LN; Mauch-P; Elias-A; Kadin-ME; Wheeler-C AD: Hematology-Oncology Division, Brigham and Women's Hospital, Boston, MA, USA. SO: Blood. 1998 Jan 15; 91(2): 717-23 AB: We performed a retrospective analysis of 35 patients with primary diffuse large B-cell lymphoma of the mediastinum treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) plus autologous hematopoietic cell transplantation to Patients transplanted in first response had an estimated 5-year PFS rate of 83%, compared with 58% and 27% for primarily refractory and relapsed patients, respectively (P = .02). The strongest predictor of PFS was chemotherapy responsiveness immediately before transplantation. Sehn-LH; et al., Blood. 1998 Jan 15; 91(2): 717-23 NHL: CHT sensitive relapse PARMA protocol 215 pats at relapse DHAP x 1 BM harvesting DHAP x 1 Responders (109) N.R. out DHAP x 4 Philip N Engl J Med 333, 1540, 1995 ABMT NHL: CHT sensitive relapse Follow up median 63 months ABMT DHAP number 49 37 toxic deaths 4/49 (8,2% ) 0 RC+RP 84% 44% 5 years EFS 46% 12% p = 0.001 5 years OS 53% 32% p = 0.038 Philip N Engl J Med 333, 1540, 1995 ABMT vs CHT in relapsed CHT sensitive NHL Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globale Per il futuro dovremmo condurre studi che consentano di stabilire se la tossicità può essere ridotta dall'impiego di cellule staminali periferiche e di fattori di crescita Philip N Engl J Med 333, 1540, 1995 Gianni A.M. et al. N Engl J Med 336, 1290, 1997 MACOP-B HDS-CHT RC 70% 96% P=0.001 FFP 49% 84% P<0.001 FFR 70% 88% P=0.055 EFS 49% 76% P=0.004 OS 7 years 55% 81% P=0.09 HD-CHT vs MACOP-B in aggressive B-cell NHL at diagnosis High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type Gianni N Engl J Med 336, 1290, 1997 HD-CHT in poor prognosis NHL at diagnosis Two years actuarial estimates STANDARD INTENSIVE EFS 35% 61% p = 0.01 OS 35% 64% p = 0.01 Pettengell J Clin Oncol 14, 586, 1996 HD-CHT in poor prognosis NHL at diagnosis pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiore la differenza giustifica un confronto formale nell'ambito di uno studio randomizzato Pettengell J Clin Oncol 14, 586, 1996 Linfomi - EFS dalla diagnosi 100 76% 80 60 40 49% 20 p = 0.004 0 0 1 2 3 4 5 6 MACOP-B Gianni et al, N Engl J Med 336, 1290, 1997 7 HDS Linfomi - EFS dalla diagnosi 120 100 BEAM (n=61) 80 65% 60 41% 40 MACOP-B (n=60) 20 p = 0.0281 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 MACOP-B BEAM Cortelazzo Br J Haematol 99, 379, 1997 Milano Bergamo Modena 48 61 40 I o II 28% 29,5% 20% III o IV 72% 70,5% 80% BM involvement 0 24,5% 41% bulky disease 76% 79%* 55% median FU** 55 28 25 number stage Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena Linfomi Event Free Survival 100 80 60 40 20 0 0 1 2 3 CHOP - Verdonck MACOP-B Fisher 4 5 6 MACOP-B Gianni 7 8 9 MACOP-B Cortelazzo Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena gennaio 1998 10 Linfomi Event Free Survival 110 HD-CHT 100 90 80 70 60 50 CHT 40 0 1 2 3 4 5 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena 6 gennaio 1998 7 AGGRESSIVE REAL Working Formulation Kiel Lineage Follicular center (grade III) D. Follicular predominantly large cell Centroblastic (follicular) B Mantle cell E: Diffuse small cleaved cells Centrocytic B Centroblastic (diffuse) B Large cell. sclerosing B cell lympohoma of mediastinum B Diffuse large B-cell F. Diffuse mixed small and large cell G. Diffuse large cell H. Large cell immunoblastic Primary mediastinal (thymic) B cell G. Diffuse large cell AGGRESSIVE REAL Working Formulation Kiel Lineage Peripheral T-cell F. Diffuse mixed small and large cell G. Diffuse large cell H. Large cell immunoblastic Lymphoepiteliod, pleiomorphic (small. medium or large cell) T Angioimmunoblastic T cell Angioimmunoblastic T Adult T cell lymphoma/leukemia Pleiomorphic (small, medium or large cell HTLV +) T Angiocentric Intestinal T cell Pleiomorphic (small, medium or large cell T AGGRESSIVE REAL Working Formulation Kiel Lineage Anaplastic large cell H. Large cell immunoblastic Large cell anaplastic (Ki-1+) T (70%) null (30%) Lymphoblaastic lymphoma I. Lymphoblastic Lymphoblastic T (90%) B (10%) J. Small non cleaved cell; Burkitt’s Burkitt’s B (95%) T (5%) Lymphoblastic Leukemia Burkitt’s HDT + auto HSCs prolunga il DFS (studi randomizzati) • NHL at relapse (Philip et al., N Eng l J Med 333, 1540, 1995) • AML RC1 (Zittoun et al., N Engl J Med 332, 217, 1995) • MM at diagnosis (Attal et al., N Engl J Med • 335, 91, 1996) NHL at diagnosis (Gianni) N Engl J Med 336, 1290, 1997 TI: Chlorambucil/prednisone vs. CHOP in symptomatic low-grade non-Hodgkin's lymphomas: a randomized trial from the Lymphoma Group of Central Sweden. AU: Kimby-E; Bjorkholm-M; Gahrton-G; Glimelius-B; HagbergH; Johansson-B; Johansson-H; Juliusson-G; Jarnmark-M; Lofvenberg-E; et-al AD: Dept of Medicine, Danderyd Hospital, Sweden. SO: Ann-Oncol. 1994; 5 Suppl 2: 67-71 AB: Two hundred fifty-nine previously untreated patients with low-grade non-Hodgkin's lymphomas (NHLs), Ann Arbor stages III and IV, entered a randomized multicenter trial comparing the therapeutic effect of chlorambucil/prednisone (ChP) vs. CHOP. All patients had symptomatic disease. ChP CHOP N. 132 127 R.R. (CR+PR at 8 months) p < 0.01 36% 60% 3 -year survival n.s. 59% 64% 5-year survival n.s. 41% 44% *corrected 5-year survival n.s. 49% 54% median survival months n.s. 46 52 The median survival time from diagnosis was 68 months, with no differences between the treatment groups. In all histological subgroups (CLL, IC, CC, and CB-CC), a higher remission rate was seen with the CHOP regimen but with no statistically significant influence on survival. Comparing patients below and above 65 years of age, no significant difference in survival was noted between the two treatment groups. The results do not support the use of intensive chemotherapy as first-line therapy in symptomatic low-grade NHL. Kimby-E et al., Ann-Oncol. 1994; 5 Suppl 2: 67-71 BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors. Caballero-MD, et al. Bone-MarrowTransplant. 20, 451, 1997 AB: Patients with NHL (n = 112) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14): 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted Only two of the 11 patients transplanted with resistant disease achieved CR. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma. TI: Results of high-dose therapy and autologous bone marrow/stem cell transplantation during remission in poor-risk intermediate- and high-grade lymphoma: international index high and highintermediate risk group. AU: Nademanee-A; et al. AD: Department of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA, USA. - Bone Marrow Transplant Programme , Stanford University Medical Center, Stanford, CA SO: Blood. 1997 Nov 15; 90(10): 3844-52 AB: We have conducted a pilot study to investigate the role of high-dose therapy and autologous bone marrow/stem cell transplantation (ASCT) during first patients number 42 median age 33 (16-56) follicular large cell diffuse mixed diffuse large cell immunoblastic 6 5 21 10 stage III-IV bulky > 8 cm 37 (88%) 36 (86%) IPI High IPI HI 25 (60%) 17 (40%) Nademanee, Blood 90, 3844, 1997 Thirty-nine were transplanted in first complete remission and 13 in first partial remission after conventional therapy. Conditioning regimens consisted of total body irradiation (TBI) administered as a single fraction 750 cGy in 3 patients and in fractionated doses for a total of 1,200 cGy in 44 patients, in combination with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide. Five patients with prior radiotherapy received 450 mg/m2 carmustine instead of TBI. Stem cell sources were either bone marrow and/or peripheral blood. No in vitro purging Nademanee-A; was used. et al., Blood. 1997 Nov 15; 90(10): 3844-52 FU median 44 months (1-113) estimated 3-year OS 84% (95% CI 70% to 92%) estimated 3-year DFS 82% (95% CI, 68% to 91%) •These results suggest that high-dose therapy and ASCT during first remission may improve the survival and prognosis of patients with poor-risk intermediate- and high-grade lymphoma. •A prospective randomized study comparing high-dose therapy and ASCT with conventional chemotherapy in IPI high-risk patients with aggressive non-Hodgkin's lymphoma should be undertaken. Nademanee-A; et al., Blood. 1997 Nov 15; 90(10): 3844-52 EFS 100 80 60 40 52 patients 20 0 0 1 2 3 4 5 6 7 Nademanee A., et al. Blood 90, 3844, 1997 8 9 10 standard intensive n. median age centroblastic immunoblastic T cell unclassified Ki-1 other bulky 18/33 stage IV 25/33 34 49 (19-60) 18 2 4 5 3 2 22/34 27/34 33 37 (23-60) 19 1 3 8 1 1 Pettengel J Clin Oncol 14, 586, number median age standard 60 49(19-60) intensive 61 45 (18-60) large cleaved (G) l.c. with LG component immunoblastic anaplastic 37 5 16 2 37 6 7 11 stage II stage III-IV bulky > 10cm bone marrow adverse features 0-1 adverse features 2-3 17 43 26 10 16 44 18 43 Cortelazzo 31 Br J 15 Haematol 23 99, 379, 38 1997 CHOP m-BACOD ProMACE number 218 age (median) (19-79) >65 24 Bulky % 225 223 233 56 (15-79) 26 57 (18-81) 25 54 (17-81) 27 57 40 41 41 40 Marrow % 25 26 27 27 LDH >250 % 45 43 42 43 MACOP-B CytaBOM WF group D-E Fisher, NEJM 328, 1002, 1993 14 15 15 14 standard (50) intensive (48) age group G group H T cell 35 (17-60) 88% 12% 0 34 (18-59) 91% 10% 0 stage I-II stage III-IV 32% 68% Gianni et al, 28% NEJM 336, 72% 1290, 1997 Marrow Bulky 0 70% 0 76% IPI L-IL IPI HI-H 2% 74% 0 94% TI: Autologous stem cell transplantation for aggressive non-Hodgkin's lymphomas in first complete or partial remission: a retrospective analysis of the outcome of 52 patients according to the ageadjusted International Prognostic Index. AU: Fanin-R; Silvestri-F; Geromin-A; Infanti-L; Sperotto-A; Cerno-M; Stocchi-R; Savignano-C; RinaldiC; Damiani-D; Baccarani-M AD: Department of Medical and Morphological Research, University Hospital, Udine, Italy. SO: Bone-Marrow-Transplant. 1998 Feb; 21(3): 263-71 Fifty-two consecutive patients, aged less than 60 years, with intermediate- or high-grade NHL, and at least one of the following adverse risk factors: bulky disease, B symptoms or Ann Arbor stage III-IV, and at least a PR after CHT (and radiotherapy (RT) on residual mediastinal mass when required), underwent ASCT conditioned with BAVC. Sixty-five percent (33/52) of the patients achieved CR after CHT; 69% (36/52) after CHT + RT; 90% (47/52) after CHT +/- RT + ASCT. One death during conditioning and three major toxic events after ASCT were recorded. Overall survival (OS) is 98% at 37 months (16-88); disease-free survival (DFS) is 100% Fanin-R. et al., Bone-Marrow-Transplant. 1998, 21, at 27 months (7-82). Comparing the observed results with those expected if patients were treated only with CHT, the sequential treatment including ASCT conferred an advantage in terms of CR rate of 14, 23 and 54%, respectively, in the low-intermediate (LI), highintermediate (HI) and high (H)-risk groups, respectively. The 2-year OS advantage is 10, 21, 31 and 63%, respectively, and the 2-year DFS advantage is 12, 26, 38 and 39%, respectively. Even more striking is the 5-year projected advantage in the number of patients alive without disease, even when considering only the low (L) (P < 0.0001) and the LIBone-Marrow-Transplant. (P < 0.0001) risk groups. Fanin-R. et al., 1998, 21, •For patients in the higher (HI + H) risk groups, ASCT should be included in the initial plan of treatment as consolidation of first CR or PR •The differences seen in this study suggest a formal comparison in a randomized study also for patients in the LI risk group. Fanin-R. et al., Bone-Marrow-Transplant. 1998, 21, 263 Università di Modena - Azienda Policlinico Dipartimento di Scienze Mediche, Oncologiche e Radiologiche Pazienti 130 LNH 39,2% Leucemie 10,8% Altri 5,4% mdH 7,7% MM 8,5% 5-10-98 Ca mammella 28,5% LINFOMI - Trapianto autologo 1 pazienti 51 sesso maschi femmine 30 21 età media mediana range 42 43 15-65 Dipartimento di Oncoematologia - Università di Modena ottobre LINFOMI - Trapianto autologo 2 Tipo istologico (WF): A-B-C D-E-F-G H-I-J Linea 9 (17,6%) 31 (60,7%) 11 (21,5%) B T nd 39 8 4 Dipartimento di Oncoematologia - Università di Modena ottobre LINFOMI - Trapianto autologo 3 stadio II 7 III 12 (13.7%) (23,5%) IV 32 (62.7%) Bulky 33/50 (66%) Midollo + 19/46 (41,3%) Dipartimento di Oncoematologia - Università di Modena ottobre Prospective randomized trial by the NHL Cooperative Study Group: 221 patients with intermediate- high grade NHL (Working Formulation F, G, H, K): 3 years CR OS PFS MACOP-B ProMACE-MOPP 52% 49% 52% 45% 36% 36% Conclusion: NO significant differences Sertoli MR et al. J Clin Oncol 12, 1366, 1994 MACOP-B +/- radiatio therapy fo diffuse olarge cell lymphoma. Analysis of the stanford results according to prognostic indices. n 3 year FFP 47 52% Compared to historical CHOP data , MACOP-B does not appear to improve outcome for patients with poor prognostic features Bartlett NL, et al Cancer 71, 4034, 1993 Intermediate- high grade NHL 4 years n CR RFS ProMECE-CytaBOM MACOP-B 106 104 62% 67% 59% 69% p 0.11 Silingardi V. et al, Leuk-Lymphoma 17, 313, 1995 LINFOMI - Trapianto autologo 4 Linea prima 45 recidiva 6 Regime BEAM HDS TBI-Cy altro Dipartimento di Oncoematologia - Università di Modena 41 7 1 2 ottobre Università di Modena - Azienda Policlinico Dipartimento di Scienze Mediche, Oncologiche e Radiologiche 5-10-98 Linfomi 51 1 36 7 ABMT BM+PBPC CD34+ selected PBPC 7 LINFOMI - Trapianto Università di Modena - Azienda Policlinico Dipartimento di Scienze Mediche, Oncologiche e Radiologiche Trapianti 148 2,7 6,76 5,41 85,14 ABMT BM+PBPC CD34+ selected PBPC 5-10-98 LINFOMI - Trapianto autologo 6 Stato pre-trapianto Risposta Valutati 44 RC 27 (61,3%) VGPR 6 (13,6%) RP 6 (13,6%) Refractory 1 Valutati 47 RC 46 (97,8%) RP 1 n.v. (HDS) 7 Dipartimento di Oncoematologia - Università di Modena n.v. (F.U.) 5 ottobre LINFOMI - Trapianto autologo Pazienti 51 FU (dal trapianto) mesi mediana 21 (1-41) vivi 45/51 (88%) vivi RC vivi Rec 43 (84%) 2 (4%) deceduti 6/51 (12%) T.R.M. D.R.M. 1 (2%) 5 (10%) Totale recidive 7/51 (14%) Dipartimento di Oncoematologia - Università di Modena ottobre Linfomi tutti 100 80 60 40 50 pazienti 20 0 1 6 12 18 24 sopravvivenza dal trapianto 30 36 42 48 EFS dal trapianto Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena ottobre 98 Linfomi - terapia di 1° linea EFS dal trapianto 100 79% 80 60 40 44 pazienti FU dal trapianto mediana 21 (2-41) 20 0 01 6 12 18 24 30 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena 36 42 ottobre 98 Linfomi - terapia di 1° linea EFS dalla diagnosi 100 80% 80 60 40 44 pazienti FU dalla diagnosi mediana 29 (6-49) 20 0 01 6 12 18 24 30 36 42 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena 48 54 ottobre 98 CD19+ Double purging (Positive/negative selection) 2,510E+08 1,000E+09 1,000E+08 PBPCs CD34+ CD34+CD19- 4,450E+06 1,000E+07 7,200E+05 1,000E+06 1,000E+05 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena 10-7-98 Diversi studi ormai suggeriscono che • HD-CHT è globalmente superiore in pazienti con malattia chemiosensibile • la tossicità è accettabile Problemi: • conferma da studi prospettici randomizzati • fattibile ? • selezione dei pazienti (overtreatment, costi) • individuare fattori di rischio • timing e strategia: all’esordio o come consolidamento? • Purging? High-Dose Therapy With Autologous Hematopoietic Rescue for Follicular Low-Grade Non-Hodgkin's Lymphoma By Philip J. Bierman, Julie M. Vose, James R. Anderson, Michael R. Bishop, Anne Kessinger, and James O. Armitage J Clin Oncol 15:445-450. Patients and Methods: We performed a retrospective review of 100 patients undergoing autologous transplantation for follicular low-grade lymphoma between April 22, 1983 and December 31, 1993. Results: Sixty-seven patients remained alive and 48 were failure-free. The median follow-up duration of surviving patients was 2.6 years (range, 1.0 to 11.7). There were eight (8%) deaths within 100 days of transplantation. Six additional patients died of nonrelapse causes up to 912 days after transplantation. Overall survival at 4 years was estimated to be 65% (95% confidence interval [CI], 54% to 75%) and failure-free survival was estimated to be 44% (95% CI, 33% to 55%). There was no definite evidence of a plateau in the failure-free survival curve. The only factor significantly associated with overall survival and failure-free survival was the number of chemotherapy regimen received before transplantation. No significant differences in outcome were observed between patients with follicular small cleaved-cell lymphoma and follicular mixed lymphoma, or between patients who received peripheral-blood stem-cell transplants and unpurged autologous bone marrow transplants. Conclusion: Prolonged failure-free survival is possible following high-dose therapy and autologous hematopoietic rescue for follicular low-grade lymphoma. It is unclear whether patients are cured with this therapy or if survival is Donor Leukocyte Infusions in 140 Patients With Relapsed Malignancy After Allogeneic Bone Marrow Transplantation By Robert H. Collins, Jr, Ofer Shpilberg, William R. Drobyski, David L. Porter, Sergio Giralt, Richard Champlin, Stacey A. Goodman, Steven N. Wolff, Wendy Hu, Catherine Verfaillie, Alan List, William Dalton, Nadine Ognoskie, Angela Chetrit, Joseph H. Antin, and John Nemunaitis Patients and Methods: We surveyed 25 North American BMT programs regarding their use of donor leukocyte Results: Complete responses were observed in 60% (95% confidence interval [CI], 51.9% to 68.1%) of chronic myelogenous leukemia (CML) patients who received DLI and did not receive pre-DLI chemotherapy; response rates were higher in patients with cytogenetic and chronic-phase relapse (75.7%; 95% CI, 68.2% to 83.2%) than in patients with accelerated-phase (33.3%; 95% CI, 19.7% to 46.9%) or blastic-phase (16.7%; 95% CI, 1.9% to 31.9%) relapse. The actuarial probability of remaining in complete remission at 2 years was 89.6%. Complete remission rates in acute myelogenous leukemia (AML) (n = 39) and acute lymphocytic leukemia (ALL) (n = 11) patients who had not received pre-DLI chemotherapy were 15.4% (95% CI, 9.6% to Hyper-CVAD and High-Dose Methotrexate/Cytarabine Followed by Stem-Cell Transplantation: An Active Regimen for Aggressive Mantle-Cell Lymphoma By Issa F. Khouri, Jorge Romaguera, Hagop Kantarjian, J. Lynn Palmer, William C. Pugh, Martin Korbling, Fredrick Hagemeister, Barry Samuels, Alma Rodriguez, Sergio Giralt, Anas Younes, Donna Przepiorka, David Claxton, Fernando Cabanillas, and Richard Champlin Purpose: Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (HyperCVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. Patients and Methods: Forty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor Results: Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received CHOP-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. Conclusion: The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL. J Clin Oncol 16:3803-3809. International Prognostic Index (I.P.I.) Fattore assente presente stadio LDH performance status I-II normali 0-1 III-IV elevate 2o> Categoria - rischio basso int. basso int. alto alto 0 1 2 3 RC OS 5 anni 92% 78% 57% 46% 83% 69% 46% 32% Shipp et al., NEJM 329, 387-394. 1993 NHL - Overall Survival 100 90 80 70 60 50 40 30 20 10 0 high intermediate and high risk patients High dose Standard 64% 49% p = 0.4 24 48 72 96 120 Haioun et al, J Clin Oncol 18, 3025, 2000 144 Fisher R.I. et al. 3 years est. O.S. DFS toxic deaths ProMACe-C ytaBOM 50% 46% 3% MACOP-B 50% 41% 6% m-BACOD 52% 46% 5% CHOP 54% 41% 1% N Engl J Med 328, 1002, 1993 Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 6 years est. O.S. PFS ProMACe-CytaB OM 46% 34% MACOP-B 41% 32% m-BACOD 40% 36% CHOP 42% 33% Linfomi - EFS dalla diagnosi 100 76% 80 60 40 49% 20 p = 0.004 0 0 1 2 3 4 5 6 MACOP-B Gianni et al, N Engl J Med 336, 1290, 1997 7 HDS Fisher R.I. Cancer Chemother Pharmacol 1997, 40 suppl:S42-6 Poiche la quota di pazienti guariti dalla chemioterapia convenzionale è <50%, sono giustificati approcci terapeutici sperimentali per migliorare la nostra possibilità di curare la malattia se un paziente non è elegibile o non vuole partecipare ad uno studio clinico, il CHOP per quanto inadeguato possa essere rimane il "gold standard" BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors. Caballero-MD, et al. Bone-MarrowTransplant. 20, 451, 1997 AB: Patients with NHL (n = 112) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14): 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors. Caballero-MD, et al. Bone-MarrowTransplant. 20, 451, 1997 AB: Patients with NHL (n = 112) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14): 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted Only two of the 11 patients transplanted with resistant disease achieved CR. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma. Gianni A.M. et al. N Engl J Med 336, 1290, 1997 MACOP-B HDS-CHT RC 70% 96% P=0.001 FFP 49% 84% P<0.001 FFR 70% 88% P=0.055 EFS 49% 76% P=0.004 OS 7 years 55% 81% P=0.09 Only two of the 11 patients transplanted with resistant disease achieved CR. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma. 6 year OS PFS ProMACE CytaBOM MACOP-B m-BACOD CHOP 46% 41% 40% 42% 34% 32% 36% 33% Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S42 6 year OS PFS ProMACE CytaBOM MACOP-B m-BACOD CHOP 46% 41% 40% 42% 34% 32% 36% 33% Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S42 Quali approcci sperimentali? 1. aumentare la dose intensity dei farmaci già in uso nei protocolli standard 2. Terapia sovramassimale e rescue con progenitori emopoietici autologhi (midollo o periferiche) 3. Nuovi farmaci (ndr) oggi: monoclonali allogenico Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S42 Quali approcci sperimentali? 1. aumentare la dose intensity dei farmaci già in uso nei protocolli standard 2. Terapia sovramassimale e rescue con progenitori emopoietici autologhi (midollo o periferiche) 3. Nuovi farmaci (ndr) oggi: monoclonali allogenico Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S42 • Se un paziente non vuole partecipare ad uno studio clinico, il CHOP rimane il gold standard • poiché i pazienti guariti dalla chemioterapia sono <50%, sono giustificati approcci terapeutici sperimentali per migliorare la nostra possibilità di curarare la malattia Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S • Se un paziente non vuole partecipare ad uno studio clinico, il CHOP rimane il gold standard • poiché i pazienti guariti dalla chemioterapia sono <50%, sono giustificati approcci terapeutici sperimentali per migliorare la nostra possibilità di curarare la malattia Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S Philip et al., N Eng l J Med 333, 1540, 1995) 215 patients at relapse DHAP BM harvesting DHAP N.R. out responders (109) DHAP X 4 NHL: PARMA protocol ABMT ABMT vs CHT in relapsed CHT sensitive NH • rispetto alla terapia convenzionale il trapianto autologo porta ad un aumento della OS e della EFS • per il futuro dovremmo condurre studi che consentano di stabilire se la tossicità può essere ridotta dall’impiego di cellule staminali Philip NEJM 333, 1540, 1995 periferiche e di fattori di crescita NHL: CHT sensitive relapse Follow up median 63 months ABMT DHAP number 49 37 toxic deaths 4/49 (8,2% ) 0 RC+RP 84% 44% 5 years EFS 46% 12% p = 0.001 5 years OS 53% 32% p = 0.038 Philip N Engl J Med 333, 1540, 1995 • There is no information from any of the previously mentioned studies to suggest that ABMT adds any benefit to the initial treatment of low-risk patients with aggressive NHL. • However, when the IPI was retrospectively applied to the GELA LNH-87 study, a failure-free and overall survival benefit was demonstrated far the high-intermediate and high-risk groups (Haioun C, et al. Survival benefit of high-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol —a group d’Etude des lymphomes de l’Adulte study. J Clin Oncol 2000, 18:3025-3O. • A retrospective subset analysis of the Italian trial yielded similar results (Santini G., et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin’s Iymphoma results of a prospective randomized trial by the non-Hodgkin’s lymphoma cooperative study group. J Clin Oncol 1998; l6: 2796-2802). Richard I. Fisher, J Natl Cancer Inst 93:4, 2001 • There is no information from any of the previously mentioned studies to suggest that ABMT adds any benefit to the initial treatment of low-risk patients with aggressive NHL. • However, when the IPI was retrospectively applied to the GELA LNH-87 study, a failure-free and overall survival benefit was demonstrated far the high-intermediate and high-risk groups (Haioun C, et al. Survival benefit of high-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol —a group d’Etude des lymphomes de l’Adulte study. J Clin Oncol 2000, 18:3025-3O. • A retrospective subset analysis of the Italian trial yielded similar results (Santini G., et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin’s Iymphoma results of a prospective randomized trial by the non-Hodgkin’s lymphoma cooperative study group. J Clin Oncol 1998; l6: 2796-2802). Richard I. Fisher, J Natl Cancer Inst 93:4, 2001 Survival benefit of High-Dose Therapy in Poor-Risk Aggressive Non-Hodgkin’s Lymphoma: Final Analysis of the Prospective LNH87-2 Protocol. A Groupe d’Etude desLymphomes de l’Adulte Study Haioun C, Lepage E, Gisselbrecht C et al. J Clin Oncol 18, 3025, 2000 - consolidative sequential CHT (ifosfamide, etoposide, asparaginase, and cytarabine) vs - HDT (CBV regimen) followed by stem-ceIl transplantation Survival benefit of High-Dose Therapy in Poor-Risk Aggressive Non-Hodgkin’s Lymphoma: Final Analysis of the Prospective LNH87-2 Protocol. A Groupe d’Etude desLymphomes de l’Adulte Study Haioun C, Lepage E, Gisselbrecht C et al. J Clin Oncol 18, 3025, 2000 - consolidative sequential CHT (ifosfamide, etoposide, asparaginase, and cytarabine) vs - HDT (CBV regimen) followed by stem-ceIl transplantation aggressive NHL • in first complete remission after induction • higk/intermediate and high-risk patients identified by the age-ad justed internationai prognostic index. •median follow-up of 8 years •final analysis aggressive NHL • in first complete remission after induction • higk/intermediate and high-risk patients identified by the age-ad justed internationai prognostic index. •median follow-up of 8 years •final analysis Bianco e nero, 150 dpi, jpeg media Coiffier Coiffier