GRADO INTERMEDIOD follicolare, prevalenza di grandi celluleE diffuso, a piccole cellule clivateF diffuso, misto a piccole e grandi celluleG diffuso a grandi cellule

ALTO GRADOH immunoblasticoI linfoblasticoJ piccole cellule non clivate (burkitt)

BASSO GRADO A piccoli linfociti B follicolare, prevalentemenete a piccole cellule clivate C follicolare misto, piccole cellule clivate e grandi cellule

B-Cell Lymphoma Precursor B-lymphoblasticSmall lymphocytic (CLL)LymphoplasmacyticMantle cellFollicle center, follicular

Grade 1*Grade 2*Grade 3*

Follicle center diffuse, small cellMarginal zone B-cell, MALT typeMarginal zone B-cell, nodalMarginal zone B-cell, splenicHairy cell leukemia PlasmacytomaDiffuse large B-cellDiffuse mediastinal large B-cellBurkitt’sHigh grade B-cell, Burkitt-likeUnclassifiable low gradeUnclassifiable high grade

Table 1. International Lymphoma Study Group Classification

T/NK-Cell LymphomaPrecursor T-lymphoblasticT-cell chronic lymphocytic leukemiaLarge granular lymphocyte leukemiaMycosis fungoidesPeripheral T cell, unspecifiedMedium-sized Mixed medium and large cellLarge cellLymphoepithelioidHepatosplenicSubcutaneous panniculiticAngioimmunoblasticAngiocentric, nasalIntestinalAdult T-cell lymphoma/leukemiaAnaplastic large cell (including null phenotype)Anaplastic large cell, Hodgkin’s-likeUnclassifiable low gradeUnclassifiable high grade

Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918

International Prognostic Index (I.P.I.)

Fattore assente presente

stadio I-II III-IVLDH normali elevateperformance status 0-1 2 o >

Categoria - rischio

RC OS 5 anni

basso 0 92% 83%int. basso 1 78% 69%int. alto 2 57% 46%alto 3 46% 32%

Shipp et al., NEJM 329, 387-394. 1993

OS and IPIAge adjusted index, patients < 69 (n = 1274)

Shipp N Engl J Med 329, 987, 1993

28-2-99

12 24 36 48 600

10

20

30

40

50

60

70

80

90

100

L Li Hi H noi OS dal trapianto

SONO TROPPPO BASSE

OS and IPIAge adjusted index, patients < 69 (n = 1274)

Shipp N Engl J Med 329, 987, 1993

28-2-9912 24 36 48 60

0

10

20

30

40

50

60

70

80

90

100

L Li Hi H noi OS dal trapiantoSONO TROPPPO BASSE

Linfomi - EFS dalla diagnosi39 patients with no or 1 risk factors I.P.I.

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

120

MACOP-B BEAM

p = 0.82679

79%

75%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=23)

MACOP-B (n=16)

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

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

Fisher N Engl J Med 328, 1002, 1993

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 inferioriil CHOP rimane il miglior trattamento oggi disponibile per pazienti con LNH in stadio avanzato a grado di malignità medio/ alto

Cancer Chemother Pharmacol 1997, 40 suppl:S42-6

Fisher R.I.

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.N Engl J Med 328, 1002, 1993

3 years est. O.S. DFS toxic deaths

ProMACe-CytaBOM

50% 46% 3%

MACOP-B 50% 41% 6%

m-BACOD 52% 46% 5%

CHOP 54% 41% 1%

3 years est. O.S. DFStoxic

deaths

ProMACe-CytaBOM

50% 46% 3%

MACOP-B 50% 41% 6%

m-BACOD 52% 46% 5%

CHOP 54% 41% 1%

Fisher R.I. et al.

N Engl J Med 328, 1002, 1993

6 years est. O.S. PFS

ProMACe-CytaBOM

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-CytaBOM

46% 34%

MACOP-B 41% 32%

m-BACOD 40% 36%

CHOP 42% 33%

Fisher R.I.

Cancer Chemother Pharmacol 1997, 40 suppl:S42-6

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

0 1 2 3 4 5 6 70

20

40

60

80

100

MACOP-B HDS

p = 0.004

76%

49%

Gianni et al, N Engl J Med 336, 1290, 1997

Linfomi - EFS dalla diagnosi

0 1 2 3 4 5 6 70

20

40

60

80

100

MACOP-B HDS

p = 0.004

76%

49%

Gianni et al, N Engl J Med 336, 1290, 1997

HD-CHT vs MACOP-B in aggressive B-cell NHL at diagnosis

Gianni N Engl J Med 336, 1290, 1997

High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type

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

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

ABMT

8 year DFS

ABMT 55% (95% CI 46%-64%)CHT 39% (95% CI 30%-48%)

CHT

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, MDCancer 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 had an especially poor outlook.

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 22.1Marginal zone B-cell, MALT 105 7.6 Peripheral T-cell 96 7.0Small B-lymphocytic (CLL) 93 6.7Mantle cell 83 6.0Primary mediastinal large B-cell 332.4Anaplastic large T/null-cell 332.4High grade B-cell, Burkitt-like 29 2.1Marginal zone B-cell, nodal 251.8Precursor T-lymphoblastic 231.7Lymphoplasmacytoid 161.2 Marginal zone B-cell, splenic 11< 1Mycosis fungoides 11< 1Burkitt’s 10 < 1

Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918

Table 6. Patient Characteristics by Histologic Type

% Median %Stage % Marr % PI % PI % 5-yr % 5-yrDiagnosis Male Age 1 or 2 Pos 0/1 4/5OAS FFS

Follicular, all grades 42 59 33 42 39 6 72

40Mantle cell 74 63 19 63 19 19 27 11Marginal zone B-cell,MALT 45 61 66 14 38 5 74 60Marginal zone B-cell, nodal 41 58 18 41 36 9 57 29Small lymphocytic 53 65 6 73 17 10 51 25Lymphoplasmacytoid 53 63 20 73 20 13 59 25Diffuse large B-cell 55 64 51 17 31 16 46

41Primary mediastinallarge B-cell 34 37 66 3 44 9 50 48Burkitt’s 89 31 56 33 44 22 44 44Burkitt-like 59 55 50 21 25 18 47 43T-lymphoblastic 74 25 13 43 35 22 26 24Peripheral T-cell,all types 56 61 18 37 14 27 25 18Anaplastic large T/null-cell 69 33 50 12 50 19 77 58

Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918

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 FFSBurkitt-like lymphomas, imprecise histologic criteria and theIndex Index Index Index lack of specific immunologic markers led to a diagnostic Consensus Diagnosis 0/1 4/5 0/1 4/5accuracy of only 53% to 65%. Further definition of theseFollicular, 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 0and other special studies to facilitate proper patient care. In Small lymphocytic (CLL) 76 38 35 13many cases, this will require communication between the Diffuse large B-cell 73 22 63 19oncologist, the surgeon, and the pathologist. Primary mediastinal large B-cell 77 0 69 0The 13 major types of NHL shown in Fig 1 made up over High grade B-cell, Burkitt-like 71 0 71 0Precursor T-lymphoblastic 29 40 29 40 90% of the cases in our study, with diffuse large B-cellPeripheral T-cell, all types 36 15 27 10 lymphoma and follicular lymphoma comprising over 50%Anaplastic large T/null-cell 81 83 49 83 of the cases and the newly recognized entities comprising21% of the cases (Table 3). The clinical features of the Abbreviations: PI, International Prognostic Index; OAS, overall sur-vival;FFS, failure-free survival; CLL, chronic lymphocytic leukemia. various lymphoma types were remarkably different, as were

Blood, Vol 89, No 11 (June 1), 1997: pp 3909-3918

Linfomi Event Free Survival

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

CHOP - Verdonck MACOP-B Gianni MACOP-B Cortelazzo

MACOP-B Fisher

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena gennaio 1998

Linfomi Event Free Survival

0 1 2 3 4 5 6 740

50

60

70

80

90

100

110

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena gennaio 1998

HD-CHT

CHT

Cancer Chemother Pharmacol 1997, 40 suppl:S42-6

Fisher R.I.

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-MOPPMACOP-BCR 49.1% 52.3% 3-year OS 45.2% 52.3%3-yearPFS 36.4% 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 trials showing that the new-generation aggressive regimens are no better than previous ones.

Sertoli-MR; et-al J-Clin-Oncol. 1994 12(7): 1366

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

PARMA protocol

NHL: CHT sensitive relapse

Philip N Engl J Med 333, 1540, 1995

215 pats at relapse

DHAP x 1

BM harvesting

DHAP x 1Responders (109)

N.R.out DHAP x 4 ABMT

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

NHL: CHT sensitive relapse

Follow up median 63 months

Philip N Engl J Med 333, 1540, 1995

Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globalePer 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

ABMT vs CHT in relapsed CHT sensitive NHL

STANDARD INTENSIVE

EFS 35% 61% p = 0.01

OS 35% 64% p = 0.01

HD-CHT in poor prognosis NHL at diagnosis

Two years actuarial estimates

Pettengell J Clin Oncol 14, 586, 1996

HD-CHT in poor prognosis NHL at diagnosis

Pettengell J Clin Oncol 14, 586, 1996

pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiorela differenza giustifica un confronto formale nell'ambito di uno studio randomizzato

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

0 1 2 3 4 5 6 70

20

40

60

80

100

MACOP-B HDS

p = 0.004

76%

49%

Gianni et al, N Engl J Med 336, 1290, 1997

HD-CHT vs MACOP-B in aggressive B-cell NHL at diagnosis

Gianni N Engl J Med 336, 1290, 1997

High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

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

NHL: CHT sensitive relapse

Follow up median 63 months

Philip N Engl J Med 333, 1540, 1995

Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globalePer 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

ABMT vs CHT in relapsed CHT sensitive NHL

STANDARD INTENSIVE

EFS 35% 61% p = 0.01

OS 35% 64% p = 0.01

HD-CHT in poor prognosis NHL at diagnosis

Two years actuarial estimates

Pettengell J Clin Oncol 14, 586, 1996

HD-CHT in poor prognosis NHL at diagnosis

Pettengell J Clin Oncol 14, 586, 1996

pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiorela differenza giustifica un confronto formale nell'ambito di uno studio randomizzato

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

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

NHL: CHT sensitive relapse

Follow up median 63 months

Philip N Engl J Med 333, 1540, 1995

Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globalePer 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

ABMT vs CHT in relapsed CHT sensitive NHL

STANDARD INTENSIVE

EFS 35% 61% p = 0.01

OS 35% 64% p = 0.01

HD-CHT in poor prognosis NHL at diagnosis

Two years actuarial estimates

Pettengell J Clin Oncol 14, 586, 1996

HD-CHT in poor prognosis NHL at diagnosis

Pettengell J Clin Oncol 14, 586, 1996

pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiorela differenza giustifica un confronto formale nell'ambito di uno studio randomizzato

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

Follicular low grade lymphoma

Patients No 915 years survival 66%median overall survival 111 months

5 years survivalsex male 57%

female 73% 0.03age < 70 67%

> 70 28% 0.004Stage I or II 89%

III or IV 57% 0.06B symptoms yes 41%

no 69% 0.03

Morel et al., Ann Hematol 66, 303, 1993

Intermediate/ high-grade lymphomasresponse rate

treatment No O.R. C.R

CHOP 225 80% 44%m-BACOD 223 82% 48%Pro-MACE-CytaBOM 233 87% 56%MACOP-B 218 83% 51%

Fisher et al, NEJM 328, 1002, 1993

Intermediate/ high-grade lymphomasresponse rate

treatment No O.R. C.R

CHOP 225 80% 44%m-BACOD 223 82% 48%Pro-MACE-CytaBOM 233 87% 56%MACOP-B 218 83% 51%

Fisher et al, NEJM 328, 1002, 1993

Intermediate/ high-grade lymphomas3 years overall survival

treatment No

CHOP 225 54%m-BACOD 223 52% P=0.9Pro-MACE-CytaBOM 233 50%MACOP-B 218 50%

Fisher et al, NEJM 328, 1002, 1993

Intermediate/ high-grade lymphomas3 years overall survival

treatment No

CHOP 225 54%m-BACOD 223 52% P=0.9Pro-MACE-CytaBOM 233 50%MACOP-B 218 50%

Fisher et al, NEJM 328, 1002, 1993

Intermediate/ high-grade lymphomas3 years D.F.S.

treatment No

CHOP 225 41%m-BACOD 223 46% P=0.35Pro-MACE-CytaBOM 233 46%MACOP-B 218 41%

Fisher et al, NEJM 328, 1002, 1993

Intermediate/ high-grade lymphomas3 years D.F.S.

treatment No

CHOP 225 41%m-BACOD 223 46% P=0.35Pro-MACE-CytaBOM 233 46%MACOP-B 218 41%

Fisher et al, NEJM 328, 1002, 1993

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi - EFS dalla diagnosiTrapianto autologo

0 1 2 3 4 5 6 70

20

40

60

80

100

Gianni Cortelazzo Modena

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

HDS Barbui Modena

number 48 61 40

stage 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%

IPI Low -LI 6% 38%

HI-High 94% 62%

median FU** 55 28 25

* bulky => 5 cm ** mesi dalla diagnosi

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Chemioterapia convenzionale

- CHOP, m-BACOD, MACOP-B, ProMACE (Fisher)SOSTANZIALMENTE SOVRAPPONIBILI

Alte Dosi

Gianni, Barbui e Modena: risultati sovrapponibili(superiori vs CHT convenzionale)

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi Event Free Survival

0 1 2 3 4 5 6 740

50

60

70

80

90

100

110

HD-CHT

CHT

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi - EFS dalla diagnosi

0 1 2 3 4 5 6 70

20

40

60

80

100

MACOP-B HDS

p = 0.004

76%

49%

Gianni

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

HD-CHT vs MACOP-B in aggressive B-cell NHL at diagnosis

Gianni N Engl J Med 336, 1290, 1997

High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi Event Free Survival

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

CHOP - Verdonck MACOP-B Gianni MACOP-B Cortelazzo

MACOP-B Fisher

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi Event Free Survival

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

CHOP - Verdonck MACOP-B Gianni MACOP-B Cortelazzo

MACOP-B Fisher

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

MACOP-B8 WEEKKS

MAD + G-CSFMACOP-B (MTZ+HD-12 WEEKS ARA-C+DZM)

PBPC

BEAM

Cortelazzo Br J Haematol 99, 379, 1997

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena - Marzo 1998

Linfomi - EFS dalla diagnosi

0 1 2 3 4 5 6 70

20

40

60

80

100

NOI Cortelazzo

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 1996-present

Stem cell source AlloBMT (n = 5) AlloSCT (n = 4).Median patient age (yrs) 27 (23-41) 30 (21-35)

Conditioning regimen CBV (n = 3), Bu-Cy (n = 3), Bu-Cy (n = 2) other (n =

1)

Status at transplant Refr (n = 1) Rel 2 or 3 (n = 4)rel 2/3 (n = 2),

other (n = 2)Prior autologous BMT 4/5 3/4

Outcome Expired 5/5 Alive 4/4 (4 within 6 mos) (2 in

remission) Median follow-up (mos) n.a. 7 (2-10)

P. Anderlini, e t al. EBMT 1998

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, FK506-based 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 6diffuse mixed 5diffuse large cell 21immunoblastic 10

stage III-IV 37 (88%)bulky > 8 cm 36 (86%)

IPI High 25 (60%)IPI HI 17 (40%)

Nademanee, Blood 90, 3844, 1997

standardintensiven. 34 33median age 49 (19-60) 37 (23-60)

centroblastic 18 19immunoblastic 2 1T cell 4 3unclassified 5 8Ki-1 3 1other 2 1bulky 22/3418/33stage IV 27/3425/33

adverse features 2 23/34 15/33adverse features 3 11/34 18/33

Pettengel J Clin Oncol 14, 586, 1996

standard intensivenumber 60 61median age 49(19-60) 45 (18-60)

large cleaved (G) 37 37l.c. with LG component 5 6immunoblastic 16 7anaplastic 2 11

stage II 17 18stage III-IV 43 43bulky > 10cm 26 31bone marrow 10 15adverse features 0-1 16 23adverse features 2-3 44 38

Cortelazzo Br J Haematol 99, 379, 1997

CHOP m-BACOD ProMACEMACOP-BCytaBOM

number 225 223 233218age (median) 56 (15-79) 57 (18-81) 54 (17-81) 57 (19-79) >65 26 25 27

24

Bulky % 40 41 41 40

Marrow % 25 26 27 27

LDH >250 % 45 43 42 43

WF groupD-E 14 15 15 14

F-G-H 81 82 81 82

J 5 4 4 4

Fisher, NEJM 328, 1002, 1993

standard (50) intensive (48)

age 35 (17-60) 34 (18-59)group G 88% 91%group H 12% 10%T cell 0 0

stage I-II 32% 28%stage III-IV 68% 72%

Marrow 0 0Bulky 70% 76%

IPI L-IL 2% 0IPI HI-H 74% 94%

Gianni et al, NEJM 336, 1290, 1997

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 large-cell lymphoma to determine whether complete-remission rates, survival, and toxicity differed when patients were treated with CHOP as compared with m-BACOD.

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): 1342-9

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 intermediate-grade NHL treated with CHOP versus those treated with MACOP-B, in a multicenter, randomized controlled trial performed by 22 centers of the Australian and New Zealand Lymphoma Group (ANZLG).

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 be

compared.

Cooper-IA; et al. J-Clin-Oncol. 1994 Apr; 12(4): 769-78

CASISTICA

• Pazienti 17– sesso

• maschi 9

• femmine 8

• Età– media 39 (20-58)– mediana 41

CASISTICA

• Stato al trapianto• RC 1

10• RP 5• Recidiva >2 2

• Patologia• LNH

11• MdH 2• LLA 2• LMA 1• MM 1

PATOLOGIE

LNH64%

MdH12% MM

6%

LA18%

LINFOMI - Trapianto autologo 1

pazienti 39

sesso maschi 19femmine 20

età media 42mediana 43range 20-65

follow up media 13 (1-29)mesi mediana 11

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Università di Modena

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; Reyes-F 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) followed by autotransplantation in patients with aggressive non-Hodgkin's lymphoma in first complete remission.

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 DFS OS

CBV 59% 65%CHT 39% 52%

P = .01 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; Preti-RA; 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 of these 11 in PR achieved a durable CR with the second transplant.

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): 449-54

BEC-2 BCNU 400 mg/m2 day -5VP-16 1800 mg/m2 day -5cyclophosphamide 2500 mg /m2 days -5 and -4

TMJ Thiotepa 250 mg/m2 days -7, -6, -5Mitoxantrone 40 mg/m2 day -7Carboplatin 330 mg/m2 days -7, -6, -5

Ahmed-T; et al. Bone-Marrow-Transplant. 1997 Mar; 19(5): 449-54

CONDIZIONAMENTO

• BEAM 12• CBV 1• BuCy 1• MTM 2• HD L-PAM 1

REGIME DI CONDIZIONAMENTO

RISULTATI

• ATTECCHIMENTO 17/17 (100%)

• VIVI 17/17 (100%)– in remissione 15/17– in recidiva 2/17 (12%)

• T.R.M. 0/17 (0%)• Follow-up

– media 5 mesi (1-10)– mediana 5 mesi

Linfomi

CHOP4 cicli

Cy 4gr/m2+G-CSF PBPCs

HD CHT(BEAM)

diagnosi

reinfusione

- conta CD34- colonie- citogenetica- diagnostica molecolare

- criopreservazione

NHL INTERMEDIATE/HIGH GRADEAUTOGRAFTING

1 2 3 4 5 6 7 8

60

40

20

80

100

CR 2 n = 472

CR 1 n = 563

36%

63%

PFS %

EBMT registry 1995

years

NHL at relapsedisease free survival

20

40

60

80

1 2 3 4 5

%

sensitive relapse

resistant relapse

years after transplantation

6 7 8

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; Soiffer-RJ; Spector-N; Grossbard-M; Robertson-MJ; et-al AD: Division of Tumor Immunology, Dana-Farber 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 cleaved-cell [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.

Freedman-AS; et al. , J-Clin-Oncol. 1993 May; 11(5): 931-6

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.

Freedman-AS; et al. , J-Clin-Oncol. 1993 May; 11(5): 931-6

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. 1997 Oct; 3(4): 210-6

TRM 6.25% median follow-up 18.8 months (4-44)OS at 18 months 78% (95% CI 37-90%) RFS at 18 months 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 long-term 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 May; 19(9): 883-90

TRM 4.4%. 5-year EFS 34% (95% CI 24-44%)median FU 3 years (range 0-7.5 years).

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; 19(9): 883-90

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 determine outcome and prognostic features for progression-free survival (PFS).

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

PARMA protocol

NHL: CHT sensitive relapse

Philip N Engl J Med 333, 1540, 1995

215 pats at relapse

DHAP x 1

BM harvesting

DHAP x 1Responders (109)

N.R.out DHAP x 4 ABMT

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

NHL: CHT sensitive relapse

Follow up median 63 months

Philip N Engl J Med 333, 1540, 1995

Rispetto alla chemioterapia convenzionale, il trapianto autologo di midollo osseo porta ad un aumento della sopravvivenza libera da eventi e della sopravvivenza globalePer 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

ABMT vs CHT in relapsed CHT sensitive NHL

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

Gianni N Engl J Med 336, 1290, 1997

High dose sequential therapy is superior to standard dose MACOP-B for patients with diffuse large cell lymphoma of the B-cell type

STANDARD INTENSIVE

EFS 35% 61% p = 0.01

OS 35% 64% p = 0.01

HD-CHT in poor prognosis NHL at diagnosis

Two years actuarial estimates

Pettengell J Clin Oncol 14, 586, 1996

HD-CHT in poor prognosis NHL at diagnosis

Pettengell J Clin Oncol 14, 586, 1996

pazienti che ricevono chemioterapia ad alte dosi hanno un EFS superiorela differenza giustifica un confronto formale nell'ambito di uno studio randomizzato

Linfomi - EFS dalla diagnosi

0 1 2 3 4 5 6 70

20

40

60

80

100

MACOP-B HDS

p = 0.004

76%

49%

Gianni et al, N Engl J Med 336, 1290, 1997

Linfomi - EFS dalla diagnosi

0 6 12 18 24 30 36 42 48 54 60 66 72 78 840

20

40

60

80

100

120

MACOP-B BEAM

p = 0.0281

65%

41%

Cortelazzo Br J Haematol 99, 379, 1997

BEAM (n=61)

MACOP-B (n=60)

Milano Bergamo Modena

number 48 61 40

stage 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

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena

Linfomi Event Free Survival

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

CHOP - Verdonck MACOP-B Gianni MACOP-B Cortelazzo

MACOP-B Fisher

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena gennaio 1998

Linfomi Event Free Survival

0 1 2 3 4 5 6 740

50

60

70

80

90

100

110

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena gennaio 1998

HD-CHT

CHT

AGGRESSIVE

REAL Working Formulation Kiel Lineage

Follicular center D. Follicular Centroblastic B(grade III) predominantly (follicular)

large cell

Mantle cell E: Diffuse small Centrocytic Bcleaved cells

F. Diffuse mixedsmall and large cell

Diffuse large G. Diffuse large Centroblastic BB-cell cell (diffuse)

H. Large cellimmunoblastic

Primary mediastinal G. Diffuse large Large cell. B(thymic) B cell cell sclerosing B

cell lympohomaof mediastinum

AGGRESSIVE

REAL Working Formulation Kiel Lineage

Peripheral F. Diffuse mixed Lymphoepiteliod,T-cell small and large cell pleiomorphic (small. T

G. Diffuse large cell medium orH. Large cell large cell)immunoblastic

Angioimmunoblastic Angioimmunoblastic TT cell

Adult T cell Pleiomorphic Tlymphoma/leukemia (small, medium or

large cell HTLV +)

Angiocentric Pleiomorphic TIntestinal T cell (small, medium or

large cell

AGGRESSIVE

REAL Working Formulation Kiel Lineage

Anaplastic H. Large cell Large cell T (70%)large cell immunoblastic anaplastic null (30%)

(Ki-1+)

Lymphoblaastic I. Lymphoblastic Lymphoblastic T (90%)lymphoma B (10%)

LymphoblasticLeukemia

Burkitt’s J. Small non cleaved Burkitt’s B (95%) cell; Burkitt’s T (5%)

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; Hagberg-H; 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) 36% 60% p < 0.01

3 -year survival 59% 64%n.s.

5-year survival 41% 44%n.s.

*corrected 5-year survival 49% 54%n.s.

median survival months 46 52n.s.

*After correction for intercurrent deaths

Kimby-E et al., Ann-Oncol. 1994; 5 Suppl 2: 67-71

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-Marrow-Transplant. 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 with active disease.

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.

Caballero-MD, et al. Bone-Marrow-Transplant. 20, 451, 1997

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 high-intermediate 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, CASO: 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 complete or partial remission in 52 patients with poor-risk aggressive lymphoma..

patients number 42

median age 33 (16-56)

follicular large cell 6diffuse mixed 5diffuse large cell 21immunoblastic 10

stage III-IV 37 (88%)bulky > 8 cm 36 (86%)

IPI High 25 (60%)IPI HI 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 was used.Nademanee-A; 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

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

Nademanee A., et al. Blood 90, 3844, 1997

52 patients

standardintensiven. 34 33median age 49 (19-60) 37 (23-60)

centroblastic 18 19immunoblastic 2 1T cell 4 3unclassified 5 8Ki-1 3 1other 2 1bulky 22/3418/33stage IV 27/3425/33

adverse features 2 23/34 15/33adverse features 3 11/34 18/33

Pettengel J Clin Oncol 14, 586, 1996

standard intensivenumber 60 61median age 49(19-60) 45 (18-60)

large cleaved (G) 37 37l.c. with LG component 5 6immunoblastic 16 7anaplastic 2 11

stage II 17 18stage III-IV 43 43bulky > 10cm 26 31bone marrow 10 15adverse features 0-1 16 23adverse features 2-3 44 38

Cortelazzo Br J Haematol 99, 379, 1997

CHOP m-BACOD ProMACEMACOP-B CytaBOM

number 225 223 233218age (median) 56 (15-79) 57 (18-81) 54 (17-81) 57 (19-79) >65 26 25 27

24Bulky % 40 41 41 40

Marrow % 25 26 27 27

LDH >250 % 45 43 42 43

WF groupD-E 14 15 15 14

F-G-H 81 82 81 82

j 5 4 4 4

Fisher, NEJM 328, 1002, 1993

standard (50) intensive (48)

age 35 (17-60) 34 (18-59)group G 88% 91%group H 12% 10%T cell 0 0

stage I-II 32% 28%stage III-IV 68% 72%

Marrow 0 0Bulky 70% 76%

IPI L-IL 2% 0IPI HI-H 74% 94%

Gianni et al, NEJM 336, 1290, 1997

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 age-adjusted International Prognostic Index.

AU: Fanin-R; Silvestri-F; Geromin-A; Infanti-L; Sperotto-A; Cerno-M; Stocchi-R; Savignano-C; Rinaldi-C; 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% at 27 months (7-82). Fanin-R. et al., Bone-Marrow-Transplant. 1998, 21,

263

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), high-intermediate (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 LI (P < 0.0001) risk groups. Fanin-R. et al., Bone-Marrow-Transplant. 1998, 21,

263

•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 PoliclinicoDipartimento di Scienze Mediche, Oncologiche e Radiologiche

Leucemie10,8%

LNH39,2%

mdH7,7%

MM8,5%

Ca mammella28,5%

Altri5,4%

Pazienti 130

5-10-98

pazienti 51

sesso maschi 30femmine 21

età media 42mediana 43range 15-65

LINFOMI - Trapianto autologo 1

ottobre 98

Dipartimento di Oncoematologia - Università di Modena

Tipo istologico (WF):

A-B-C 9 (17,6%)D-E-F-G 31 (60,7%) H-I-J 11 (21,5%)

Linea B 39T 8nd 4

LINFOMI - Trapianto autologo 2

Dipartimento di Oncoematologia - Università di Modena ottobre 98

stadio II 7 (13.7%)III 12 (23,5%)

IV 32 (62.7%)

Bulky 33/50 (66%)

Midollo + 19/46 (41,3%)

LINFOMI - Trapianto autologo 3

Dipartimento di Oncoematologia - Università di Modena ottobre 98

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 52% 52% 36%ProMACE-MOPP 49% 45% 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 106 62% 59%MACOP-B 104 67% 69%

p 0.11

Silingardi V. et al, Leuk-Lymphoma 17, 313, 1995

Linea prima 45

recidiva 6

Regime BEAM 41HDS 7TBI-Cy 1altro 2

LINFOMI - Trapianto autologo 4

ottobre 98

Dipartimento di Oncoematologia - Università di Modena

1

7

7

36ABMT

BM+PBPC

CD34+ selected

PBPC

Università di Modena - Azienda PoliclinicoDipartimento di Scienze Mediche, Oncologiche e Radiologiche

5-10-98Linfomi 51

LINFOMI - Trapianto autologo 5

2,7

6,76

5,41

85,14

ABMT

BM+PBPC

CD34+ selected

PBPC

Università di Modena - Azienda PoliclinicoDipartimento di Scienze Mediche, Oncologiche e Radiologiche

5-10-98

Trapianti 148

Stato pre-trapianto Risposta

Valutati 44 Valutati 47RC 27 (61,3%) RC 46 (97,8%)VGPR 6 (13,6%) RP 1RP 6 (13,6%) Refractory 1

n.v. (HDS)7 n.v. (F.U.) 5

LINFOMI - Trapianto autologo 6

ottobre 98

Dipartimento di Oncoematologia - Università di Modena

Pazienti 51FU (dal trapianto) mesi mediana 21 (1-41)

vivi 45/51 (88%) vivi RC 43 (84%)vivi Rec 2 (4%)

deceduti 6/51 (12%) T.R.M. 1 (2%)D.R.M. 5 (10%)

Totale recidive 7/51 (14%)

LINFOMI - Trapianto autologo 7

ottobre 98

Dipartimento di Oncoematologia - Università di Modena

Linfomi tutti

1 6 12 18 24 30 36 42 480

20

40

60

80

100

sopravvivenza dal trapianto EFS dal trapianto

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena ottobre 98

50 pazienti

Linfomi - terapia di 1° lineaEFS dal trapianto

0 1 6 12 18 24 30 36 420

20

40

60

80

100

79%

44 pazientiFU dal trapianto mediana 21 (2-41)

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena ottobre 98

Linfomi - terapia di 1° lineaEFS dalla diagnosi

01 6 12 18 24 30 36 42 48 540

20

40

60

80

10080%

44 pazientiFU dalla diagnosi mediana 29 (6-49)

Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena ottobre 98

CD19+Double purging (Positive/negative selection)

10-7-98Dipartimento di Scienze Mediche, Oncologiche e Radiologiche - Modena

2,510E+08

4,450E+06

7,200E+05

1,000E+05

1,000E+06

1,000E+07

1,000E+08

1,000E+09

PBPCs

CD34+

CD34+CD19-

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?

• non è la soluzione per pazienti con malattia refrattaria

High-Dose Therapy With Autologous Hematopoietic Rescue forFollicular 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 patientswas 2.6 years (range, 1.0 to 11.7). There were eight (8%) deaths within 100 days of transplantation. Six additional patientsdied 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%). Therewas no definite evidence of a plateau in the failure-free survival curve.

J Clin Oncol 15:445-450.

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 forfollicular low-grade lymphoma. It is unclear whether patients are cured with this therapy or if survival is prolonged.

J Clin Oncol 15:445-450.

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 infusions(DLI). Reports of 140 patients were thus available for analysis.

Results: Complete responses were observed in 60% (95% confidence interval [CI], 51.9% to 68.1%) of chronicmyelogenous leukemia (CML) patients who received DLI and did not receive pre-DLI chemotherapy; response rates werehigher in patients with cytogenetic and chronic-phase relapse (75.7%; 95% CI, 68.2% to 83.2%) than in patients withaccelerated-phase (33.3%; 95% CI, 19.7% to 46.9%) or blastic-phase (16.7%; 95% CI, 1.9% to 31.9%) relapse. Theactuarial probability of remaining in complete remission at 2 years was 89.6%. Complete remission rates in acutemyelogenous leukemia (AML) (n = 39) and acute lymphocytic leukemia (ALL) (n = 11) patients who had not receivedpre-DLI chemotherapy were 15.4% (95% CI, 9.6% to 21.2%) and 18.2% (95% CI, 6.6% to 29.8%), respectively.Complete remissions were also observed in two of four assessable myeloma patients and two of five assessablemyelodysplasia patients. Complications of DLI included acute graft-versus-host disease (GVHD) (60%; 95% CI, 51.4% to68.6%), chronic GVHD (60.7%; 95% CI, 50.3% to 71.1%), and pancytopenia (18.6%; 95% CI, 12.2% to 25.0%).

Conclusion: DLI results in complete remissions in a high percentage of patients with relapsed chronic-phase CML.Complete remissions are observed less frequently in patients with advanced CML and acute leukemia. GVHD and pancytopenia occur commonly; GVHD is highly correlated with response.

J Clin Oncol 15:433-444.

Hyper-CVAD and High-Dose Methotrexate/Cytarabine Followed by Stem-Cell Transplantation: An Active Regimen for AggressiveMantle-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.

J Clin Oncol 16:3803-3809.

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 (Hyper-CVAD) thatalternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated withhigh-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 Arborstage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients hadnodular, and two patients had blastic variants. J Clin Oncol 16:3803-3809.

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).

J Clin Oncol 16:3803-3809.

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 forpreviously untreated patients with MCL.

J Clin Oncol 16:3803-3809.

International Prognostic Index (I.P.I.)

Fattore assente presente

stadio I-II III-IVLDH normali elevateperformance status 0-1 2 o >

Categoria - rischio

RC OS 5 anni

basso 0 92% 83%int. basso 1 78% 69%int. alto 2 57% 46%alto 3 46% 32%

Shipp et al., NEJM 329, 387-394. 1993

0102030405060708090

100

24 48 72 96 120 144

High dose

Standard

NHL - Overall Survival

49%

64%

p = 0.4

high intermediate and high risk patients

Haioun et al, J Clin Oncol 18, 3025, 2000

3 years est. O.S. DFStoxic

deaths

ProMACe-CytaBOM

50% 46% 3%

MACOP-B 50% 41% 6%

m-BACOD 52% 46% 5%

CHOP 54% 41% 1%

Fisher R.I. et al.

N Engl J Med 328, 1002, 1993

6 years est. O.S. PFS

ProMACe-CytaBOM

46% 34%

MACOP-B 41% 32%

m-BACOD 40% 36%

CHOP 42% 33%

Fisher R.I.

Cancer Chemother Pharmacol 1997, 40 suppl:S42-6

Linfomi - EFS dalla diagnosi

0 1 2 3 4 5 6 70

20

40

60

80

100

MACOP-B HDS

p = 0.004

76%

49%

Gianni et al, N Engl J Med 336, 1290, 1997

Cancer Chemother Pharmacol 1997, 40 suppl:S42-6

Fisher R.I.

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-Marrow-Transplant. 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 with active disease.

BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors. Caballero-MD, et al. Bone-Marrow-Transplant. 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 with active disease.

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.

Caballero-MD, et al. Bone-Marrow-Transplant. 20, 451, 1997

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.

Caballero-MD, et al. Bone-Marrow-Transplant. 20, 451, 1997

Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S42

6 year OS PFS

ProMACE CytaBOM 46% 34%MACOP-B 41% 32%m-BACOD 40% 36%CHOP 42% 33%

Fisher, Cancer Chemother Pharmacol 1997, 40:suppl S42

6 year OS PFS

ProMACE CytaBOM 46% 34%MACOP-B 41% 32%m-BACOD 40% 36%CHOP 42% 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:

monoclonaliallogenico

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:

monoclonaliallogenico

• 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 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 S42

NHL: PARMA protocol

215 patients at relapse

DHAP

DHAP

BM harvesting

N.R. out responders (109)

DHAP X 4 ABMT

Philip et al., N Eng l J Med 333, 1540, 1995)

• 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

periferiche e di fattori di crescitaPhilip NEJM 333, 1540, 1995

ABMT vs CHT in relapsed CHT sensitive NHL

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

NHL: CHT sensitive relapse

Follow up median 63 months

Philip N Engl J Med 333, 1540, 1995

• There is no information from any of the previously mentioned studies tosuggest that ABMT adds any benefit to the initial treatment of low-riskpatients with aggressive NHL.

• However, when the IPI was retrospectively applied to the GELA LNH-87study, a failure-free and overall survival benefit was demonstrated far thehigh-intermediate and high-risk groups (Haioun C, et al. Survival benefit ofhigh-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: finalanalysis of the prospective LNH87-2 protocol —a group d’Etude deslymphomes 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 bonemarrow transplantation for advanced diffuse non-Hodgkin’s Iymphoma -results of a prospective randomized trial by the non-Hodgkin’s lymphomacooperative 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 tosuggest that ABMT adds any benefit to the initial treatment of low-riskpatients with aggressive NHL.

• However, when the IPI was retrospectively applied to the GELA LNH-87study, a failure-free and overall survival benefit was demonstrated far thehigh-intermediate and high-risk groups (Haioun C, et al. Survival benefit ofhigh-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: finalanalysis of the prospective LNH87-2 protocol —a group d’Etude deslymphomes 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 bonemarrow transplantation for advanced diffuse non-Hodgkin’s Iymphoma -results of a prospective randomized trial by the non-Hodgkin’s lymphomacooperative 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 AggressiveNon-Hodgkin’s Lymphoma: Final Analysis of the Prospective

LNH87-2 Protocol. A Groupe d’Etude desLymphomes del’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 AggressiveNon-Hodgkin’s Lymphoma: Final Analysis of the Prospective

LNH87-2 Protocol. A Groupe d’Etude desLymphomes del’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