AML - CR1

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