Allogeneic stem cell
transplantation
in myeloma
The Dutch
Dutch Hovon Experience
Experience
Henk Lokhorst
Date
HOVON xx DIAG
1
Overall survival
HOVON 24:from allogeneic
Allo-SCT astransplantation
part of first line therapy
Allo-SCT vs control (=Auto/IFN)
after myeloablative conditioning with Cyclo/TBI
100
e
Auto/IFN
75
ercentagp 50
TRM 30%
Allo-SCT
ulativem
Cu
25
N
O
Allo-SCT
56
32
Auto/IFN
73
24
Logrank P 001
<.
0
0
12
24
months 36
At risk:
Allo-SCT 56
37
20
7
Inferior survival from Allo Transplantation as compared
Auto/IFN 73
60
36
25
Date
to Auto Tr
HOVON xx
ansplantation DIAG
+ maintenance (JCO 2005)
2
HOVON 54 study 2003 2006
-
· Patients included
included in the Hovon
Hovon 50 study with an
HLA-identical family donor could proceed to
tandem autologous, non-myeloablative Allo-
SCT following conditioning with low dose TBI
only
· 93 patients were included, 87 eligible for
evaluation
· Analysis as of May 2007: Toxicity, PFS, OS
Date
HOVON xx DIAG
3
HOVON 50/54
VAD (3x)
TAD (3x)
vs
Randomization n=450
Iv push
Thal 200-
200 400mg/daily
CAD +G
+ G-CSF
Cyclo/adria/dex
Thalidomide
50
/d
mg
il
a y
HDM 1x
200mg/m2
H5
Hovon 4
54
-IFN
HLA-id Sib<66 yrs
Thrice/weekly
N=93
Nl
NonmyeloST
ST
200cGy
Date
HOVON xx DIAG
4
Patient characteristics
all risk groups included
· Age median
median
54 years (33
(33-65)
· Male/ Female
55/45 %
· ß-
ß 2 micr
micr. median
median
3 1
.
· 13 + 4/14 (FISH)
20%
· PR + CR before NMA 79 %
· CR before
NMA 16%
Date
HOVON xx DIAG
5
Toxicity
· Acute GvHD grade 2-4
20%
grade 3
5%
5%
grade 4
5%
· Extensive chronic GVHD
54%
· TRM (mainly
(mainly GvHD)
10%
Date
HOVON xx DIAG
6
Response,
p, PFS and OS
· CR following NMA increased from 14% to
41%
· Actuarial 3-year estimate of PFS of 48%
· Actuarial 3-year estimate of OS of 82%
Date
HOVON xx DIAG
7
Progression Free Survival
Progression free survival
100
.
|
|
|
||
e
75
|
75
| || | | ||| ||||| | | || ||| | ||
||||| | |
| |
percentag
50
|||
tive
Cumula
25
Actuarial 3-year estimate of PFS of 48%
N
p
87
37
0
0
12
24
months 36
At risk:
87
63
33
8
Date
HOVON xx DIAG
8
Progression Free Survival
Progression free survival
100
e
75
HO54
percentag
50
tive
HO24
Cumula
25
versus Hovon 24: myeloablative conditioning
N
p
HO24
61
51
HO54
87
37
0
0
12
24
months 36
At risk:
HO24 61
42
27
19
HO54 87
63
33
8
11 May 2007 - 14:15:10
Date
HOVON xx DIAG
9
Overall Survival
Survival
Overall survival
100
.
|
|
|
|| | | | |
|
| || | || || | || |
| | | | | |
| | | | |
|||| | |
|| |
| | |
e
75
percentag
50
tive
Cumula
25
Actuarial 3-year estimate of OS of 82%
N
d
87
16
0
0
12
24
months 36
At risk:
87
68
42
16
Date
HOVON xx DIAG
10
Overall Survival
Survival
Overall survival
100
HO54
e
75
HO24
percentag
50
tive
Cumula
25
versus Hovon 24: myeloablative conditining
N
d
HO24
62
42
HO54
87
16
0
0
12
24
months 36
At risk:
HO24 62
45
35
31
HO54 87
68
42
16
11 May 2007 - 14:15:10
Date
HOVON xx DIAG
11
Overall Survival
Overall survival
HO54-allo vs HO50-maintenance: 87 patients per group
100
HO50
HO54
e
75
50
vepercentag
versus Hovon 50 maintenance
Cumulati
25
N
d
HO50
87
14
HO54
87
16
0
0
12
24
months 36
At risk:
HO50 87
65
31
6
HO54 87
68
42
16
11 Date
May 2007 - 14:15:10
HOVON xx DIAG
12
Progression free survival
Progression free survival
HO54-allo vs HO50-maintenance: 87 patients per group
100
e
75
50
HO54
vepercentag
HO50
Cumulati
25
N
p
versus Hovon
Hovon 50 maintenance
HO50
87
33
HO54
87
37
0
0
12
24
months 36
At risk:
HO50 87
59
24
3
HO54 87
63
33
8
11 Date
May 2007 - 14:15:10
HOVON xx DIAG
13
Prognostic factors
No impact on OS and PFS of
· Response after
after NMA
NMA (CR vs
vs PR)
PR)
· Presence of acute GvHD
· Pf
Presence of ch
i
ron c GvHD
HD
· High ß2-microglobulin
· 13 + 4/14
Date
HOVON xx DIAG
14
First Conclusions
Conclusions
· Longer Follow-up is needed to "confirm" the
Italian data.
- Careful donor versus no-donor evaluation to be done
· So far no plateau in PFS
·
post transplant therapy: maintenance ?
Date
HOVON xx DIAG
15
HOVON 76 /GMMG
VAD (3x)
PAD (3x)
vs
Hovon 65/GMMGHD-4
Iv push
Thal 200-
200 400mg/daily
HDM
200mg/m2
No HLA-id Sib
HLA-id Sib
NonmyeloST
200cGy
Bortezomib vs
Phase II
80
vs
thalidomide
study
patients
Lenalidomide
Date
10
HOVON
mg/daily
xx DIAG
16
Novel agents, GvM and GvHD
· Both Bortezomib and thalidomid (analogs) are
remarkably effective in combination with DLI (Blood
2006)
· Hovon trial: DLI + Bortezomib; no stimulation of GvHD
· Lenalidomide as single agent is highly effective in
relapsed patients after nonmyeloablative Allo-SCT
- Response 11/11
- may reduce persistent chronic GvHD
- may strongly
strongly enhance
enhance GvHD
GvHD
Date
HOVON xx DIAG
17
patient thalid
bortez
DLI
GvHD response
1
+
++
PR
2+
+
+
PR
3
+
+
+
PR
4+
PR
5+
+
+
PR
6
++
VGPR
7
+
+
+
VGPR
8
+
+
+
PR
9
+
+
+
VGPR
10
+
+
+
PR
Date
HOVON xx DIAG
18
11
+
+
+
PR
Immune modulating effects of
lenalidomide in Allo setting
· Patients were "sampled"
sampled before and
during lenalidomide therapy for relapsed
refractory my
yyeloma following non
myeloablative Allo
- no significant changes in lymphocyte subsets
- Decrease in IL-10 and TNF- plasma levels
- Strong increase of regulatory T cells ( Foxp3
cells)
Date
HOVON xx DIAG
19
patient T.
FoxP3
20
ls
prednisone
son
cel 10
10
itive
8
pos
6
%
4
2
0
-21
0
22
50
129
days
Revlimid
Date
HOVON xx DIAG
20
Final conclusions
· Longer follow-up of the Hovon 54 and EBMT study is
needed to establish a beneficial Graft versus Myeloma
effect of nonmyeloablative Allo-SCT
· A great step forward is the strongly reduced TRM
associated with non myelo-ablative conditioning
· This creates a window for post transplant therapies
like maintenance with novel agents and cellular therapie
like pre-
pre emptive DLI
DLI
· Creates?
Date
HOVON xx DIAG
21
Acknowledgments
Transplantation centers HOVON
Myeloma Research Lab UMCU
Amsterdam: AMC, VUMC
Tineke Aarts
Rotterdam: Erasmus MC
Michael van het Veer
Nijmegen. AMCN
Robbert Spaapen
Maastricht: AZM
Kelly van den Oudenalder
Utrecht: UMCU
Berris van Kessel.
Lij i
n e Bogers
M.J.Kersten, S.Zweegman,
Ellen van der Spek
M Zijlmans, P.Sonneveld
Monique |Minnema
R.Raymakers
Henk Lokhorst
G.Bos. H. Schouten
Tuna Mutis,
H.Lokhorst, M Minnema
Date
HOVON xx DIAG
22