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Donor lymphocyte iinfusion
nfusion and other
p
posttransplant
osttransplant s
strategies
trategies after allogeneic
stem cell transplantation
ttransplantation
in Multiple Myeloma
Nicolaus M. Kröger

Background:
Allogeneic Stem Cell Tr
T ansplantation
r
T
T--Cells
Cells
Graft versus Host (GvHD)
Donor
D
Ri
Rec
R
i i
p
t
en
CD34+ Stemcells
Graft versus Myeloma
Myeloma--Effect
Effect

Background
Donor T--lymphocytes
lymphocytes can be given in
patients after allogeneic stem cell
transplantation and can induce tumor
regression
g
by
gy immunomediated
targeting of tumor/host specific
antig
anti ens
g

Donor lymphocyte infusion in multiple
myeloma
1. DLI for
for relapse after standard
standard conditioning
2. DLI for relapse after reduced intensity
conditioning
3. DLI as maintenance therapy or to improve
remission status
4. Novel agents as salvage or maintenance
therapy
5. DLI in combination with novel agents
6. Perspectives of posttransplant strategies after
after
allograft in myeloma

Donor lymphocyte infusion for relapse after
standard conditioning
- n=54
- median age : 52 years (34
(34--68
68 y)
- median time to allo SCT : 20 months (only siblings)
s
siblings)
- Dose: 1 x 106 CD3/kg to 5 x 108 CD3+/kg
- starting dose for the majority: 1 x 107 CD3+/kg
Lokhorst et al., 2004

Donor lymphocyte infusion for relapse after
standard conditioning
- acute GvHD: 57%
grade II:
26%
d
gra e III/IV:
III/IV 20%
- chronic GvHD: 47%
limited:
17%
extensive: 30%
Lokhorst et al., 2004

Donor lymphocyte infusion for relapse after
standard conditioning
- Response: ORR: 52%
- PR: 35% and CR: 17%
- factors for response:
acute GvHD:
80% ORR
no acute GvHD: 33% ORR p<0001
chronic GvHD: 73%
no cGvHD: 37% p>0.001
- no if
in
i
l
fluence
fl
on response by T-
ll
-ce
ce dose (p=0.
0 4)
4
4)
(40 pts received some form of reinduction
chemotherapy)
Lokhorst et al., 2004

Survival after DLI according resonse
Prop
Pro ortion
p
of survival
1,0
0,8
CR
0,6
0,4
02
0,
0 2
,
PR
0,0
20
40
60
80
100
120
Months

Donor lymphocyte infusion for relapse after
standard conditioning
· Other studies for relapsed patients:
ORR: 40
40--67%
67% and CR: 19
19--30%
30%
· Acute GvHD: 52
52--56%
56% and cGvHD: 26
26--44%
44%
· Strong correlation between
b
between response and
and
occurrence of GvHD
(Lokhorst et al 1997, Ve
V rdonck
e
et al 1996, Salama 2000, Ay
A uk
y
et al., 2004, Tr
T icot 1996,
Bertz et l
a .,
l 199 )
7
· CD8
CD8--depleted
depleted DLI: ORR: 71% and CR: 43%
acute GvHD: 50%
( Alyea et al 2001)

Donor lymphocyte infusion for relapse after
reduced intensity conditioning
conditioning
n=21
GH
Gv
G
D
GH
HD nach DL
D I
L
DLI: II - IV:n
IV
= 7 (30%)
(30%)
III / IV:n
IV
= 2 (9%)
1,0
Response: 42%
0,8
CR:n = 16%; PR:n = 26%
06
0,
0 6
,
unrelated n=10
0,4
p=0,01
ltd
0,2
rel
re a
l t
a e
t d
e
n=11
n=1
0,0
0
050
50
100
150
Tag
Ta e
g
Ay
A uk
y
et al., Leukemia 2004

Donor lymphocyte infusion for relapse after
reduced intensity conditioning
conditioning
European survey: 8 centers
n= 48 with relapsed myeloma after
after RIC
R
RIC conditioning
Median age: 55 y (r: 36
36--70y)
70y)
Overall response rate: 38%: PR: 19% and CR 19%
Acute GvHD
G
GvHD II
II-IV:
IV 38%
chronic GvHD: 42% (extensive cGvHD: 10%)
van de Donk et al., 2006

Donor lymphocyte infusion for relapse after
reduced intensity conditioning
conditioning
Response according GvHD:
acute GvHD :
no: 21% ORR
yes: 67% ORR
chronic GvHD:
no: 19% ORR
yes: 63% ORR
van de Donk et al., 2006

Donor lymphocyte infusion for relapse after
reduced intensity conditioning
conditionin
yg
Proportion of survival
1,0
08
0,
0 8
,
PR + CR
0,6
0,4
NR
0,
0 2
,
0,0
0
10
20
30
40
50
60
Months

Donor lymphocyte infusion as maintenance
therapy or
or to
tto improve
improve remission status
n=23
median DLI: 1 x 106
10 CD3+/kg (r: 5 x 105
10 to 2 x 108
10 CD3+/kg)
median time from allo SCT to 1.DLI: 211
21 days (r: 61
61--740)
740)
median number of DLIs: 2 (r: 1
1--4)
4)
status prior DLI:
DLI:
PR:
n=
n= 20
2
20
VGPR: n= 3
bt
bes
b
t response aft
fter DLI
DLI:
DLI CR:
n=15 (65%)
VGPR: n=5
NC:
n=3
aGvHD:
grade I: n=3
grade II n=4 (16%)
grade
g
III n=2 (
g(8%)
cGvHD: lim: n=4 (16%)
ext: n=2 (8%)

Allogeneic SCT followed by prophylactic
donor lymphocyte
llymphocyte infusion
iinfusion
Probability
1,0
0,8
63%
0,6
0,4
0,
0 2
,
0,0
0
1000
2000
3000
OS (days)

Allogeneic SCT followed by prophylactic
donor lymphocyte infusion
infusion
Probability
1,0
0,8
0,6
43%
0,4
0,
0 2
,
0,0
0
1000
2000
3000
EFS (days)

Allogeneic SCT followed by prophylactic
donor lym
y p
yphocy
hoc te
y
infusion
Probability
1,0
CR
0,8
52%
0,
0 6
,
0,4
No CR
25%
02
0,
0 2
,
0,0
p=0.03
0
1000
2000
3000
EFS (days)

Novel agents as salvage therapy
Thalidomide
n=31
median dose: 200mg (range: 50
50--600
600 mg)
Discontinuation due to side effects: n= 6 (19%)
(%)
(%
ORR: 29% (6 PR/ 3 VGPR)
acute GvHD II-IV : n=5
n
n=5 (16%)
OS at two years: 50%
Mohty et al., BMT 2004

Novel agents as salvage therapy
Bortezomib +/
+/-- Dexamethason
Dexamethason
Bortezomib:
1. highly active against myeloma cells
2. in animal model: reduced GvHD but retain Graft
versus leukemia effect (Sun et al. PNAS 2004) and lead
to a decreased T--helper
helper 1 response among alloreactive
T-
T lymphocytes (Blanco
(
et al. Blood 2006)
n= 23
ORR: 61%
CR: 22%
side effect: neuropathy:
n
neuropathy: 53%
thrombocytopenia: 43%
Bruno et al., Haematologica 2006

Novel agents as as maintenance therapy
Bortezomib:
Design:
Ve
V lcade 1.3 mg/m² day 1,4,8 and 11
1 (at least two
cycles) in non
non--progressing
progressing patients with residual
disease after allogeneic SCT
Median age:
49 years (r,
(r 32
32--68)
68)
HLA
HLA--sibling:
sibling:
n = 2
MUD:
n = 16
Del 13
13 positive: n=9
n = 9
Kröger et al., Exp Hem 2006

GvHD and To
T xicity
· 4 patients did not completed two cycles due to:
neuropathy grade III/IV (n=3) or abdominal
cramps, diarrhea (n=1)
GvHD:
· n = 1: skin aGvHD
aGvHD grade I to II
· n = 1: skin aGvHD (< 25%)
· n = 2: mild deterioration of pre
pre--existing
existing chronic
skin GvHD

To
T xicities according to NCI (CTC)
Gr
G ade
Gad
Ga e
d 0
Gr
G ade
Gad
Ga e
d I
Gr
G ade
Gad
Ga e
d II
Gr
G ade
Gad
Ga e
d III
Gr
G ade
Gad
Ga e
d IV
Leukocytes
11
1 ( 6 %
1 (6%)
3 (17%)
1 (6%)
2 (11%)
(1
Platelets
4 (22%)
(22%)
2(
2 11
1
(1 %
1 )
%
1%)
3 (17%)
(17%)
2(
2 11
1
(1 %
1 )
%
1%)
7 (39%)
(39%)
Neuropathy
3 (17%)
6 (33%)
6 (33%)
2 (11%)*
(1
1 (6%)*
Ft
Fa
F i
tigue
3 (17%)
(17%)
14 (78%)
1(
1 6%
6 )
%
(6%)
--
--
Diarrhea
3 (17%)
6 (33%)
9 (50%)
--
--
--
Nausea
8 (45%)
9 (50%)
1 (6%)
--
--
Renal
16 (55%)
--
--
2 (12%)
--
--
--
*Neurotoxicity grade III/IV only in pat with ongoing CSA treatment

Response
· CR: 30 %
· PR:
PR 50 %
· MR: 20 %
· After a median follow
follow--up
up of 18 months
(range, 6-24), all
all but two patients
p
patients
remained in remission

Donor lymphocyte infusion in combination
with novel agents
Tr
T eatment plan
Thalidomide 100 mg
14 days
DLI: 1 x 106
10 CD3+/kg (MUD)
or: 5 x 106 CD3+/kg (related)
Kröger et al., Blood 2004

Thalidomide and DLI
To
T xicity
o
Peripheral
Constipation Weakness
W
neuropathy
Grade 0
5
57
713
13
Grade 1
12
12
10
3
Grade 2
1
1
2

Thalidomide and DLI
Response rate
CR:
6
6/18
/18
33%
PR:
PR
4/18
22%
67% (ORR)
MR:
2/
2 1
/ 8
1
/8
12%
SD/NC:
5/18
28%
PD:
1/18
1/18
5%
Med. time to response: 108 days (36 266)

Thalidomide and DLI
afte
f r
afte
f r
afte
f r
SCT
DLI
Thal/DLI
No. of patients
18
11
11
18
18
acute GvHD
GvHD I-
I IV
10 (55%)
5 (46%)
((46%)
2(
2 1
2( 1
1
(1 %)
1%)
acute GvHD II
II--IV
IV
4 (22%)
3 (27%)
0
chr.
chr GvHD lim
4 (22%)
((22%)
4 (36%)
((36%)
7 (39%)
chr.
chr GvHD ext
1 (6%)
0
00
0

Perspectives of posttransplant strategies
after allograft
allograft in
in myeloma
m
myeloma
Identification and targeting myeloma specific
antigenes to separate Graft
Graft--versus
versus--Myeloma
Myeloma
from GvH reaction
1. myeloma specific idiotype
2. minor histocompatibility antigens
3. MUC-
MUC 1
4. RHAMM
5. Cancer
C
Cancer testis antigens

Post
Post--transplant
transplant Strategies
after allog
allo raft
g
Donor Vaccination
V
prior allo SCT
· Myeloma
Myeloma--specific
specific idiotypic determinant of
immunog
immuno lobulin
globulin-
g
-variable
variable region
g
in 5 donors:
· Immunoglobulin
Immunoglobulin--specific
specific T--cell
cell response was
seen in all patients
p
patients and
and persisted for 18
18 months
m
months
· 2/5 remained disease
disease--free
free at 7 and 8 years,
respectil
ively
Kw
K a
w k
a et
e al
a .
l ,
. 1995, Ne
N e
e l
e a
l p
a u
p et
e al
a .
l ,
. 2005

Cancer testis antigen in myeloma
A
B
C
CT10/MAGEC2
MAGEC1
72,7
MAGEA3
MAGEC2
56,4
SSX1
MAGEA3
54,5
SSX2
SSX1
34,5
SSX4
20,0
SSX3
SSX5
20,0
SSX4
SSX2
16 4
,
SSX5
BAGE
14,5
BAGE
NY-ESO-1
7,3
NY-ESO-1
ADAM2
5,5
ADAM2
LIP1
5,5
LIP1
SSX5
0,0
GAPDH
SCP1
0,0
4
7
3
5
0
6
4
0
2040
6080
100
% of MM patient BM samples expressing the CT antigen
BMT2
BMT2
BMT0
BMT0
DON2
DON0
DON0
Atanackovic et al, Blood 2007

Antibody response after allo SCT
Pre
Post
PBSCT
PBSCT
1400
NY-ESO-1
1200
LAGE1
MAGEA1
MAG
1000
MAGEA3
MAGEA4
800
OD
MAGEA10
600
SSX1
SSX2
400
SSX4
XAGE1
XAG
200
p53
0
1000
900
800
700
600
OD
500
400
300
200
100
0
1400
1200
1000
800
OD
600
400
200
Atanackovic et al, Blood 2007
0

Ta
T rgeting residual disease after
transplantation
p
in my
pyeloma
Induction with new agents
Cytoreduction (autologous SCT)
RIC allograft
Platform for MRD-targeting
gg
Posttransplantat-strategies
Drug-based:
Adoptive Immunotherapy:
Vaccination:
- Thalidomid
DLI: CD 8 depleted CD3+ cells
-mHag
- Bortezomib
- Cancer testis antigen
All
t
oreac i
tive NK
NK-Cl
Ce l
lls
- Revlimid
- Donor vaccination
Myeloma-specific CTL`s
(idiotype)

Molecular residual disease after allogeneic
stem cell transplantation
ttransplantation
Multip
Multi le
p
My
M eloma
y
py
(EBMT-Study)
Stud
PCR neg
PCR mixed PCR pos
p
No of pts
16
19
13
5 year cumulativ
risk of relapse
0%
33%
100%
Corradini et al., Blood 2003

Ta
T rgeting ,,molecular Remission"
(real
(real-
(
-time
time PCR or Plasmacell
Plasmacell--chimerism
chimerism)
PCR +
PCR -
Allograft
DLI
1.
DLI
DLI+Thal
2.
DLI
DLI+Thal
Ve
V lcade
3.
tient
DLI
t
Pa 4.
DLI
DLI+Thal
Ve
V lcade
5.
5
Ve
V lcade
6.
1
12
23
34
4
Years
Y

Acknowledgement
Bone Marrow Tr
T ansplantation
University Hospital Hamburg/Germany
H. Renges
B.
B. Fehse
N. Fehse
A. Badbaran
H. Schieder
M. Zagrivnaja
J. Panse
L. Fang
N. Stute
A. Lange
FA
F.
F A
k
yu
ML
M.
M
i
ML o
i
Lioz
Lio no
n
nov
no
H. Kabisch
T.
T Binder
R. Erttmann
Erttmann
T.
T Zabelina
Z
Zabelina
A.R. Zander

Acknowledgement
Germany
Spain
Spain
H.G. Sayer
Jena
J. Perez-Simon
Salamanca
R. Schwerdtfeger
Wiesbaden
Wiesbaden
R. Martino
Barcelona
Barcelona
M. Kiehl
Idar
Idar--Oberstein
Oberstein
J. San Miguel
Salamanca
Salamanca
J. Beyer
Marburg
M. Bornhäuser
Dresden
H. Einsele
Würzburg
Würzburg
United Kingdom
A. Zander
Hamburg
Hamburg
B. Shaw
London
ML
M.
M
i
ML
Lioznov
Hb
Ham
H
burg
b
D. Marks
Bristol
Bristol
B.Fehse
Hamburg
Hamburg
K. Peggs
London
A.Badbaran
Hamburg
Hamburg
USA
Israel
Nagler
Te
T l
e Hashomer
H. Klingemann, H. Myint
Chicago
Chicago
A.
A Shimoni
S
DA
D.
t
DA
At
k
anac
i
ov c, J. Ol
O d
Old
Ld
Lu
L d
u w
d i
Shimoni
D. Atanackovic, J. Old
ig -
Institut
New Yo
Y rk
o