Nantes
T.J. Mc Elwain, R.L. Powles
High-dose intravenous Melphalan for plasma-cell
leukemia and myeloma.
Lancet 1983;2:822-824
J.L. Harousseau, N. Milpied, R. Garand, J.H.
Bourhis
High-dose Melphalan and autologous bone
marrow transplantation in high-risk myeloma.
Br J Haematol 1987;67:493 (letter)
2 patients treated with ABMT as
consolidation after induction treatment with
HDM
HIGH-DOSE MELPHALAN PLUS GM-CSF
placebo
N = 33
HDM
140mg/m²
GM-CSF
N = 69
5µg/kg/D x 21 D
GM-CSF significantly reduced neutropenia (23.5
vs 29) but did not reduce morbidity and mortality
(11.6%) in the GM-CSF group.
If intensive therapy is indicated, support with
autologous SCT is safer despite the risk of
contamination.
Moreau JCO 1997
ASCT AFTER 1st REMISSION INDUCTION
FRENCH REGISTRY
- 133 pts (18 French centers)
- Conditioning regimen
HDM + TBI
71
HDM 140
25
-o
50
ther
8
45
40
35
30
25
20
15
10
5
CR rate 37%
0
13
36
46
17
5
- median sv from ASCT 46 months
median duration of response 35 months
Blood 1992
Most important prognostic factor :
magnitude of response after ASCT
IMPACT OF THE RESPONSE AFTER ASCT
100
90
80
CR post ASCT (N = 49)
70
60
50
40
30
PR post ASCT (N = 61)
20
10
p = 0.04
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
OBJECTIVES
1) Research LAB in NANTES
R. Bataille
2) Make any effort to create a large multicenter
group
IFM
Régis BATAILLE
MONTPELLIER
NANTES
Martine AMIOT
Hervé AVET-LOISEAU
Philippe MOREAU
Research Laboratory
Hematology Laboratory
Clinical Department
- Phenotype (C.Pellat-Deceunynck)
- Signalling pathways (M. Amiot)
- Interactions MM / BM microenvironment (S.Barille)
- Genetic changes (FISH analysis) (H Avet-Loiseau)
Better understanding of pathophysiology
Prognostic correlations
Defining novel therapeutic strategies
Phenotype
-
Expression of CD28, CD40 and CD56 is related to
disease activity and medullary homing (Pellat Blood ,
1994)
-
Role of CD40 in Human Myeloma cells (Pellat
Cancer Research, 1996) (Bergamo BJH, 1997)
-
CD130 expression is upregulated during disease
progression (Barille BJH, 1999)
-
Expression of CD20 is frequently associated with a
small mature plasma-cell morphology and t(11;14)
(Robillard Blood, 2003) (Garand Leukemia, 2003)
GENERATION OF PCs FROM MEMORY B CELLS
(D-4)
D0
D2
D4
D7
CD40L
CD40L
B
B*
Pro PB
PB
IL-2+IL-10
Pro PC
IL-2+IL-10
CD20++ 45+++
CD20++ 45+++
CD20+/- 45+++
CD20- 45++
CD20- 45++
38_ 138-
38+/- 138-
38+ 138-
38+++ 138-
38+++ 138+++
CD38
CD38
CD38
CD38
CD20
CD20
CD20
CD20
CD38
CD38
CD138
CD138
FROM MEMORY B CELLS TO PCs
BB+
pro PB
PB
pro PC
PC
S phase
CD45
Bcl-2
CD20
CD38
CD138
CD25
CD126
IL-6
In vitro stop
Normal and malignant PC
BB*
pro PB
PB
pro PC
PC
MM
CD45++CD45+/-
CD45
S phase
proliferation
Bcl-2
notype
CD20
CD138
phe
CD38
kine
CD25
CD126
Cyto response
Robillard Blood 05, in press
Jego Blood 99.94:701
Pellat-Deceunynck Blood Cells Mol Dis 04. 32:293
Pellat-Deceunynck Leukemia 98.12:31997
Bataille Immunol Rev 03. 193:105
Puthier Leukemia 99, 13:289
Jego Blood 01. 97:1817
Robillard Clin Cancer Res 98, 4:1521
Pellat-Deceunynck Hematology J 00,1:362
Pellat-Deceunynck Cancer Res 95.55:3647
Jego Leuk Res 00,24:627
Pellat-Deceunynck Blood 94.84:2597
Myeloma cells are a mix of proliferating CD45bright Bcl-2low
and non proliferating CD45low Bcl-2high cells
Normal BM
MM
R1
R1
CD38
CD38
SSC-H
r=9
SSC-H
R3
9%
R3
R3
CD138
r=22
CD45
CD45
R4
R4
R4
2%
SSC-H
SSC-H
BrdU
Bcl2
In contrast to normal BM PCs, the CD45 level of myeloma
cells in R4
is not low but negative in some patients (MFIR1 versus >1.2)
PATIENTS WITH CD45neg VS CD45low
COMPARTMENT AT DIAGNOSIS HAVE
A POOR SURVIVAL PROGNOSIS
95 patients treated by intensive chemotherapy
High dose melphalan plus stem cell transplantation
1.0
0.8
CD45 low
n=65
survival
0.6
of
0.4
p = .004
CD45 neg
0.2
Probability
n=30
0
0
600
1200
1800
2400
3200
Days
IL-6 induces CD45 and proliferation in myeloma cells
in association to CD38 decrease
CD45 neg
CD45+
IL-6
CD45
S phase
CD38
MCL-1 is an essential survival protein
for myeloma cells
-Expression of anti-apoptotic members of the Bcl-2 family
is a key process in the survival of MM cells
-Bcl-xL and Mcl-1 are upregulated by
IL-6 in MM. (Puthier BJH 1999)
HMCL
020
hours
-Signal transduction leading to this
IL-6
-
-+
upregulation involves JAK/STAT
Mcl-1 -
(Puthier Eur. J. Immunol 1999)
Bcl-x -
L
Bcl-2 -
- IFN and VEGF upregulate Mcl-1
(Puthier BJH 01,Le Gouill Blood 04)
INHIBITION OF Bcl-2, Bcl-x AND Mcl-1
L
AFTER INTRODUCTION OF SPECIFIC ASO
ASO
ASO
ASO
control
control
L
control
ASO
No
Bcl-2
ASO
ASO
Bcl-x
ASO
Mcl-1
Actin
Mcl-1
Bcl-
U266
x
Bcl-2
L
Actin
Mcl-1
Bcl-
LP-1
x
Bcl-2
L
ONLY Mcl-1 ASO INDUCES APOPTOSIS
IN MM CELLS
Mcl-1 ASO
Bcl-x ASO
L
Bcl-2 ASO
80
60
40
U266
sllec 20
+7.2 0
O
024
6
8
02
4
6
8
02
4
6
8 10 12
P
80
Afo 60
%
No ASO
40
Control ASO
LP1
20
ASO
0
0
2
4
6
8
02
4
6
8
02
4
6
8
Days after electroporation
EXPRESSION OF Mcl-1 IN NORMAL
AND MALIGNANT PLASMA CELLS
35
30
ratio
25
20
15
1
2
10
fluorescence 5
0 0
1
3
Mean
Normal M
MM
BM PC M Relaps
e
Wuillème-Toumi et al Leukemia in press 2005
THE IMPACT OF FISH ON PROGNOSIS
IN THE CONTEXT OF HDT
Fish analysis H AVET-LOISEAU (Nantes)
Facon (Blood 2001)
110 patients
(Nantes Lille)
Moreau (Blood 2002)
168 patients
(Nantes Lille)
PROGRESSION-FREE SURVIVAL
ACCORDING TO CHROMOSOME 13 DELETIONS
Progression-free
survival
1.0
Progression-free
13
O/N
survival time
median ± se (month)
0.8
no
41/68
32.6 ± 3.8
yes
33/42
16.8 ± 1.9
0.6
0.4
P = .0005
0.2
0.0
0
12
24364860
7284
time from diagnosis (month)
PROGRESSION-FREE SURVIVAL ACCORDING TO THE NUMBER OF
UNFAVORABLE FACTORS (2m > 2.5 mg/L, 13)
Progression-free
survival
1.0
Progression-free
# factors
O/N
survival time
median ± se (m)
0
11/22
37.0 ± 9.5
0.8
1
41/55
26.7 ± 3.8
2
28/33
15.2 ± 2.0
0.6
0.4
0.2
P < .0001
0.0
0
12
24364860
7284
time from diagnosis (month)
OVERALL SURVIVAL IN PATIENTS WITH t(4;14)
1.0
0.9
0.8
no t(4;14), n=145
0.7
ival
0.6
v
0.5
Sur
of
0.4
0.3
t(4;14), n=22
0.2
Probability
p=0.0016
0.1
0
0
20
40
60
80
100
OS in months
OVERALL SURVIVAL IN PATIENTS WITH t(11;14)
1.0
0.9
0.8
t(11;14), n=26
0.7
0.6
al
0.5
no t(11;14), n=141
fSurvivo
0.4
0.3
p=0.059
0.2
Probability
0.1
0
0
20
40
60
80
100
OS in months
IFM 90 Trial
200 patients < 65 y.o.
CC
HDT
p. Value
N=100
N=100
Response rate
38%
14%
<0.001
(CR + VGPR)
Median EFS
18 m
28 m
7-year EFS
8%
16%
<0.01
Median OS
44 m
57 m
7-year OS
25%
43%
<0.05
LESSONS FROM THE IFM 90 TRIAL
1) - HDT is superior to CC in terms of CR rate, EFS,
OS (at least in patients up to 65 years of age)
- These results were fully confirmed 7-years later
by the MRC7 study (NEJM 2003) and more
recently by the Italian study (Blood 2004).
ASCT is now considered as the standard of
care for patients up to 65 years of age
2) Impact of the magnitude of response on survival
IFM 95 TRIAL DESIGN
de novo MM
< 65 y
VAD x 3
SC collection
if no progression
R
HDM 140 + TBI 8g
HDM 200
N = 140
N = 142
IFM 95
RESULTS
HDM 200 is less toxic
- Significant reduction of time to hematopoietic recovery
- Significant reduction of RBC and platelet transfusions
and iv ATB
- Significant reduction of hospitalisation
- Significant reduction of grade 3/4 mucositis
- 0/142 deaths vs 5/140 with HDM 140 + TBI
IFM 95
RESULTS
HDM 200 is at least as effective
- No significant difference in response rate and
EFS
- Better overall survival
- Better salvage after relapse
IFM 95
CONCLUSIONS
- HDM 200 should be prefered to HDM 140 + TBI
and is currently used in IFM trials
- Knowing the good tolerance of HDM 200 higher
doses have been explored with encouraging
results
HDM 220 mg/m²
(Moreau BJH 1999)
HDM 220 mg/m² + Anti IL6 (Moreau BJH 2000)
IFM 99-04 trial
DOUBLE INTENSIVE THERAPY
- 97 pts (44 rel/ref MM, 53 newly diagnosed)
- 1st course = HDM 140 mg/m² without hematopoietic
support
- 2nd course
HDM 140 mg/m² + TBI + ABMT in
responding patients
only 38/69 pts responding to the 1st
course received the 2nd due to severe
myelosuppression after the 1st
- 11/22 PR
CR after the 2nd course:proof of concept ?
(Blood 1992)
THE IMPACT OF DOUBLE TRANSPLANTATION
ON CR RATE
- Feasibility of double transplants thanks to the use of
growth factors and PBSC (Vesole Blood 1994)
- CR rate increased from 24% after the first transplantation
to 43% after the second (Vesole Blood 1996)
CR 43 %
12
61
83
PR 38 %
53
84
1
TX
2nd
NR 19 %
53
14
2
Post
NR = 118
PR = 159
CR = 86
32 %
44 %
24 %
Post 1st TX
IFM 94
First randomisation : single versus double
VAD
VAD
VAD
Second randomisation : BM versus PBSC
VAD
VAD
VAD
VAD
Mel (140) + TBI
Mel (140) + PBSC
Mel (140) + TBI
BM
PBSC
(CD34+)
(CD34+)
BM
PBSC
(CD34+)
(CD34+)
IFM 94 : BM versus PBSC
BM
PBSC
P
(n=163)
(n=180)
ANC < 500
12 d
10 d
0.001
Plat < 50 000
21 d
12 d
0.001
Plat Transfusions
7
4
0.01
6-year EFS
21%
26%
NS
6-year OS
37%
50%
NS
IFM 94 : EFS
p < 0.03
median
30 months
median
25 months
20%
B
A: single transplant (N=199)
A
B: double transplant (N=200)
10%
IFM 94 : OVERALL SURVIVAL
p< 0.01
42%
B
A
21%
A: single transplant (N=199)
B: double transplant (N=200)
The only factor predicting the impact
of the 2nd ASCT is the result of the first
(n=46)
(n=128)
B
B
A
(n=81)
VGPR or CR p = 0.7
<VGPR p < 0.001
A
(n=84)
SINGLE vs DOUBLE ASCT
RANDOMIZED STUDIES
Nb of pts
Age
Results
IFM 94
399
< 61
EFS and OS
(NEJM 03)
MAG 95
227
< 56
No difference
(Turin 04)
Bologna
220
< 61
EFS
(ASH 04)
GMMG
261
< 66
EFS
(Turin 04)
Hovon
303
< 66
CR and EFS
(ASH 04)
IFM99 : FACTORS : 13 , 2 > 3 mg/l
0-1 Factor
2 Factors
VAD x 3
VAD x 3
Mel 140 + PBSC
Mel 200 + PBSC
Mel 200 + PBSC
IFM 99-02
IFM 99-03
IFM 99-04
No maintenance
HLA id sibling
No HLA id sibling
Pamidronate
Non myeloablative
Mel 200 + PBSC + anti IL6
Pamidronate
Allo BMT
+ Thalidomide
PBSC collection : IFM 99-01
Cyclo (4g/m²)
+ G-CSF
SCF
+ G-CSF
IFM 99-02
- Patients < 65 years
- 0 or 1 adverse prognostic factors (chr 13, 2 M)
VAD
VAD
VAD
SC collection
HDM 140 + AT
HDM 200 + AT
Pamidronate
Control
Pamidronate
+ Thalidomide
IFM 99-02 : PFS FORM RANDOM
Arm C
Arm A
Arm B
P < 0.01
IFM 99-02 : OVERALL SURVIVAL FROM
RANDOMISATION
IFM 99-02 : RISK OF BONE EVENTS
Arm A
P < 0.04
Arm B
Arm C
IFM 99-03 / 99-04
- < 65 years
- 2 mic > 3 mg/l + 13 (FISH)
VAD x 3
SC collection
HDM200
+ ASCT
HLA id sibling
No HLA id sibling
IFM 99-03
IFM 99-04
ATG + Bu + F
HDM 220 + Anti IL6
Allo BMT
Auto SCT
IFM 99-03 / 99-04
284 pts up to 65 y
HLA id sibling
No HLA id sibling
64 pts : 46 (72%)
220
54
Refusal
15
VAD
Death
8
HDM 200
Progression 17
Other
14
R
166
(75%)
HDM 220
HDM 220 + anti IL6
85
81
IFM 99-04
RESPONSE RATE
88%
89%
90
80
64%
70
60
51%
50
40
34%
33%
30
16%
20
14%
4%
10
PR
0
VGPR
VAD
HDM 200
HDM 220
CR
No difference between the 2 arms
IFM 99-04
1.0
0.9
0.8
OS med 39m
0.7
p = 0.53
0.6
ival
Arm B
0.5
EFS=30m
surv
of
0.4
ity
Arm A
0.3
babil
Pro
0.2
Arm A
0.1
Arm B
p = 0.59
0
0
12
24
364860
DOUBLE ASCT WITH MORE INTENSIVE 2ND
HDT IMPROVES THE OUTCOME OF POOR-RISK MM
Historical Comparison
EFS
OS
1.0
1.0
0.8
med 33
0.8
0.6
166 PTS
0.6
med 47
0.4
0.4
166 PTS
med 25
0.2
med 15
0.2
33 PTS
33 PTS
0.0
0.0
0
12
2436486
0
012
2 728
43
4
64860
728496
(month)
(month)
EFS INTENT-TO-TREAT :
IFM 99-03 VS 99-04
0.9
p = 0.70
0.8
0.7
99-04 N=220
0.6
0.5
l
0.4
Surviva
of
99-03 N=64
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
SURVIVAL INTENT-TO-TREAT :
IFM 99-03 VS IFM 99-04
1.0
0.9
p = 0.34
0.8
0.7
0.6
99-04 N=222
0.5
l
99-03 N=64
0.4
Surviva
of
ity
0.3
babil
0.2
Pro
0.1
0
012
24
36
48
60
CONCLUSION OF THE IFM TRIALS
IN THE FIELD OF HIGH-DOSE THERAPY (I)
- ASCT > CC (up to 65 y of age)
- OS is related to initial outcome
CR/VGPR should be the objective
- HDM200 is the standard conditioning regimen
prior to ASCT
- Double ASCT > single ASCT
(at least in patients with < 90% reduction of
their M-component after 1 ASCT)
CONCLUSION OF THE IFM TRIALS
IN THE FIELD OF HIGH-DOSE THERAPY (II)
Risk adapted strategy (IFM 99 trials)
- Maintenance with Thalidomide prolongs EFS in
standard risk patients
- More intense regimen is safe and effective in
poor risk patients
- Tandem auto/mini allo is not superior to double
ASCT in poor risk patients
FISH ANALYSIS OF IFM 99 TRIALS
PRELIMINARY RESULTS
Hervé Avet-Loiseau (Nantes)
1082 registered patients
983 analysed
Ficoll + CD138 purification
Del (13) = 965 pts
ploidy = 658 pts (2/3 probes)
t(11;14) = 760 pts
c-myc = 576 pts
t(4;14) =
727 pts
del(17) = 526 pts
FISH ANALYSIS
INCIDENCE OF GENETIC CHANGES
Overall
Standard risk
Poor risk
(99-02)
(99-03 99-04)
del(13)
45%
28%
100%
t(11;14)
21%
21.5%
17.5%
t(4;14)
14%
10.5%
23%
ploidy
33%
35%
21%
c-myc
13%
12%
16%
del(17p)
11%
7%
21%
t(11;14)
t(11;14)=1 (153 patients)
t(11;14)=1 (570 patients)
p=0.15
t(11;14)=1 (153 patients)
t(11;14)=1 (570 patients)
p=0.22
Del(13)
del (13) = 0
(483 patients)
del(13) =1 (436 patients)
p=4.10-6
del(13) = 0 (483 patients)
del(13) =1 (436 patients)
p=6.10-6
CORRELATIONS BETWEEN
CYTOGENETIC ABNORMALITIES
del(13) in 84% of t(4;14)
77% of del(17p)
14% are t(4;14) and del(17p)
t(4;14)
t(4;14)=0 (593 patients)
t(4;14)=1 (97 patients)
p=10-7
t(4;14)=0 (593 patients)
t(4;14)=1 (97 patients)
p=10-7
INTEGRATING NOVEL THERAPIES IN
THE DOUBLE ASCT PARADIGM
Novel Agents instead of double
AT (older patients)
Combined with double ASCT
Before AT to increase CR rate
After AT to maintain Remission
RESPONSE TO TREATMENT
IN THE IFM 99-06 TRIAL
% of patients (at 12 months)
Category of response
MP
MP-T
MEL100
Complete response
3
14
18
90%
8
51
39
50%
34
84
71
VELCADE/DEXAMETHASONE
IN NEWLY DIAGNOSED MM
- 4 consecutive 21 day cycles
Velcade 1.3 mg/m² D1, D4, D8, D11
Dexamethasone 40mg D1-D4, D9-D12 (D1-D4
for cycle 3-4)
- 48 pts med age 55 (38-71)
- 40 pts (83%) received all 16 planned injection
1 pt
received 14 injections (PN)
7 pts
received 12 injections (2 tox)
Only 3 withdrawal for toxicity
TOXICITY
INCIDENCE OF SIDE EFFECTS IN 48 PATIENTS
50
50,00
2
2
45,00
40,00
21
35,00
29
29
27
30,00
2
6
2
% of patients
25,00
19
10
6
17
20,00
Grade 4
8
2
13
Grade 3
15,00
4
4
11
25
Grade 2
10,00
4
19
2
15
17
Grade 1
13
13
5,00
9
9
0,00
GI
PN
Fa
Cu
In
Hem
Hep
NV
ti
fe
gue
t
ct
a
a
io
t
t
o
ic
n
PN : grade 3 and 4
VELCADE/DEXAMETHASONE
EFFICACY
- Stem cell collection in 45/48 pts (3 progressions)
(with G-CSF alone)
. nb of CD34+ always > 2.106 CD34+/kg
. median 6.7 (2-33.8)
. 70% > 5.106 CD34+/kg
- Response rate (all 48 pts)
. CR
21%
. VGPR
10%
. PR
35%
IFM 2005-01
Patients wiht newly diagnosed MM < 65 y.o.
R
A1
A2
B1
B2
N
VAD
Vel/Dex
VAD
Vel/Dex
OI
VAD
Vel/Dex
VAD
Vel/Dex
TC
VAD
Vel/Dex
VAD
Vel/Dex
U
VAD*
Vel/Dex*
VAD*
Vel/Dex*
DNI
1st ASCT
1st ASCT
DCEP
DCEP
.L
DCEP
DCEP
OSNO
1st ASCT
1st ASCT
C
2nd ASCT if < 90% reduction of the M-component within 3 months
* SC collection
M. Attal
T. Facon
H. Avet-Loiseau
P. Moreau
F. Garban
(94/95-02)
(99-06)
(FISH)
(95/99-06)
(99-03)
PROGNOSTIC FACTORS
RISK GROUPS
IFM (Facon 2001)
2 M + chr 13 abnormalities (FISH)
Nb adverse PF
0
1
2
(20%)
(50%)
(30%)
Median SV
111 m
47 m
25 m
HDM 220 mg/m²
Pilot study : 27 patients
( 9 primary refractory
18 relapses after HDT)
- grade 4 mucositis 63% patients
2 atrial fibrillation
- 7 CR (26%)
16 PR (59%)
Anti- IL6 murine AB (BE8)
100 mg D1 (2 hours infusion)
50 mg D2-4
+
Dex 40 mg (D1-4) + HDM 220 D5
16 pts = 10 grade 4 mucositis
13 responses (83%)
6 CR,7PR
LESSONS FROM THE IFM 94 TRIAL
- For patients up to 60 years of age double
ASCT is superior to single ASCT in terms of
EFS and OS
- At least in patients with less than 90%
reduction of the M-component 2-3 months
after one ASCT
IFM 94 : OVERALL SURVIVAL
OS if response to 1stgraft < 90%
ALL PATIENTS
P<0.01
P<0.001
A
B
DT
OS if response to 1st graft 90 %
ST
PROGRESSION-FREE SURVIVAL ACCORDING TO THE
NUMBER OF UNFAVORABLE FACTORS (2m 2.5 mg/L, 13)
Progression-free
survival
1.0
Progression-free
# factors
O/N
survival time
median ± se (m)
0
11/22
37.0 ± 9.5
0.8
1
41/55
26.7 ± 3.8
2
28/33
15.2 ± 2.0
0.6
0.4
0.2
P < .0001
0.0
0
12
24364860
7284
time from diagnosis (month)
IFM 94 TRIAL
RESPONSE RATE
Single TX
Double TX
N = 199
N = 200
HDM 140
Response
-
77
CR
-
15
CR + VGPR
-
23
HDM 140 + TBI
Response
84
89
CR
34
35
VGPR + CR
42
p = 0.15
50
IFM 99-04
1.0
0.9
0.8
0.7
median : 39 months
0.6
0.5
SURVIVAL
OS
F
O
0.4
ILITY
0.3
OBAB
median : 30 months
0.2
PR
0.1
EFS
0
012
24
36
48
60
EXPANSION OF POLYCLONAL PCs
REACTIVE PLASMACYTOSES
Reactive plasmacytoses are transient expansions of
circulating polyclonal PCs
Reactive plasmacytoses are observed in different contexts
Tumors: leukemia, lymphoma, cardiac myxoma (IL6
production)
Infection: EBV (primary or reactivation), acute
respiratory infections
Hematopoietic recovery (G-CSF) after aplasia (even in
patients with multiple myeloma)
Myeloma bone disease :
an unbalanced bone remodeling with increased osteoclastic
resorption (OPG/RANKL axis) and low bone formation
Osteoblastic cell
Myeloma cells
VLA-4, NCAM...
Decreased
Bone formation
RANKL expression
OPG production
Osteocalcin production
MIP-1
+
OPG degradation
+
TNF-
IL-6, IL-11
OPG/RANKL ratio
Osteoclastogenesis
RANKL inhibitors
Excessive
Active osteoclast
Osteoclast precursors
bone resorption
Giuliani N, Bataille R, Barillé-Nion S Blood 2001, 98(13) 3527
Barillé-Nion S, Bataille R Leuk Lymp2003 44(9)1463
OVERALL SURVIVAL IN PATIENTS WITH C13A
1.0
0.9
0.8
0.7
no del(13) , n=91
ivalv
0.6
Sur
of
0.5
del(13) , n=76
0.4
0.3
Probability
0.2
p=0.004
0.1
0
0
20
40
60
80
100
OS in months
OVERALL SURVIVAL ACCORDING TO THE NUMBER OF
UNFAVORABLE PROGNOSTIC FACTORS (2m > 2.5 mg/L, 13)
Survival
1.0
0.8
# factors
O/N
Survival time
median ± se (month)
0.6
0
2/22
> 111.
1
29/55
47.3 ± 4.6
2
22/33
25.3 ± 3.2
0.4
0.2
P < .0001
0.0
0
12
24364860
728496
time from diagnosis (month)
LONG-TERM RESULTS OF HDT
SINGLE CENTER EXPERIENCE
- 127 pts with a minimum follow-up time of 6 years
(85-95)
- 12-y OS 25%
12-y EFS 3%
- Prognostic factors association with a better
outcome - age < 55 A
- 2mic < 3 mg/l
- completion of 2nd transplant
- Patients with all favorable parameters (25% of
this group) have a 48% 10-yr OS
Moreau Leukemia 2002
FISH ANALYSIS
Moreau Blood 2002
168 patients
86 single ASCT
72 double ASCT
10 allo ASCT
117 IgH rearrangements (70%)
t(4;14)
22 (13%)
t(14;16)
4 (2%)
t(11;14)
26 (15.5%)
ch13 abnormalities
76 (45%)
Significant association between t(4;14) and ch13 abn (82%)