Strategies to improve Graft versus Myeloma
What can be learned from Donor Lymphocyte Infusions following
myeloablative and non myeloablative Allo-transplants?
Henk Lokhorst
University Hospital Utrecht,The Netherlands
Donor T cells are essential for GvM
Progression free survival from transplant
·
Negative proof: (partially)T
Hovon 24
cell depleted Allo-SCT is
inferior to Auto-PBSCT
- No improvement of remission
duration
- No increase in CR rate
Overall survival from transplantation
Hovon 24
- Inferior survival due to high TRM
(>30%)
Donor T cells are essential for GvM
·
Positive proof: DLI for relapse
following (partially)T cell
CR
depleted Allo-SCT is effective
PR
·
- Partial response
19 (35%)
- Complete response 9 (17%)
0
20
40
60
80
100
120
months
0verall
28 (52%)
1.1
1.0
.9
.8
·
Response to DLI is strongly
.7
survival
associated with the occurence
.6
.5
of GvHD (Blood 2004)
.4
.3
.2
N=54
.1
.0
0
20
40
60
80
100
120
months
DLI following non myeloablative Allo-SCT
Retrospective analysis from 9 European centers, March 2005
· DLI
92 courses (1.106-1.108 T cells/kg))
· Patients
63 patients
- Sibling donor
47
- MUD
16
- Relapse:
48
- Persistant disease:
15
· Previous conditioning NMA
- Low dose TBI (Fludarabine)
22
- Semi intensive
41
· T cell depletion
- Unmanupilated full grafts
30
- ATG/Alemtuzimab
33
DLI following non myeloablative Allo-SCT
· Patients
63
- Thalidomide added to DLI
17
- Reinduction therapy
12
· Response to DLI
PR
12 (19%)
CR
12 (19%)
Total
24 (38%)
Duration of response
1, 0
re s p d l i
cr
pr
c r- c ens or e d
0, 8
pr- c ens or e d
laiv 0,6
PR
CR
rvu
Sm 0,4
Cu
0, 2
P=0.002
days
0, 0
0, 00
300, 00
600, 0 0
900, 00
1 200, 00
1 500, 0 0
C O M P U T E
ti m e = XD A T E. T D A Y
( d at ef o l l o w u p ) - X D A T E . T D A Y ( d at ed l i )
(C O M P U T E )
Overall Survival
S u r v ival F u n c t i o n s
1, 0
0, 8
PR + CR
laiv 0,6
rvu
S
NR
m 0,4
Cu
0, 2
P=0.08
days
0, 0
0, 00
500, 0 0
100 0, 00
1500, 00
C O M P U T E
ti m e = XD A T E.T D A Y
( d at ef o llo w u p ) - X D A T E .T D A Y ( d at ed li)
(C O M P U T E )
Toxicity of DLI
· Acute GvHD
%
· Chronic GvHD %
grade
1
11
- limited
10
2
4
- extensive
33
3
8
total
43
4
2
total (1-4)
25
· TRM 10 % !
Predictive factors for response to DLI
Factors
P (univariate)
P (multivariate)
·
Conditioning regimen NMA
0.3
·
T cell depletion (ATG/anti CD52) 0.2
·
Induction therapy given
0.5
·
T cell dose of DLI
0.07
·
T cell chimerism at time of DLI
0.7
·
Thalidomide added to DLI
0.3
·
MUD donor
0.7
·
Acute GVHD I-IV after DLI
<0.001
0.012
·
Chronic GVHD after DLI
<0.001
0.021
·
Deletion of chromosome 13
0.7
DLI following non myeloablative Allo-SCT
· Response rate seems lower as compared to DLI
following (T cell depleted) ablative Allo-SCT
· Sustained remissons are rare, restricted to
patients achieving a CR
· No Graft versus Myeloma without GvHD
· Survival after DLI is remarkable! The majority of
patients however had received (and responded)
to "novel" agents
Is DLI the preferred (first) option for patients with a
relapse/persistant disease after (NMA) Allo-SCT?
· Is there a role for the novel agents like
thalidomide (analogs) & velcade after Allo-SCT ?1
· Can we improve antigen presentation to the donor
effector cells? What is the role of autologous APC
·
1 Kroger et al: Low dose thal and DLI. Blood nov.2004
·
Sun et al: Bortezomib inhibition of GVHD while sparing GVL. PNAS
may 2004
Efficacy of Thalidomide after Allo-SCT
· 17 patients ineligable for (repeated) DLI
- thalidomide starting dose 100-200 mg/day
- in case of response maintenance 50 mg/day till relapse
· Response
- PR
10/17
(60%) including
- VGPR
4/17
(24%)
· Response duration
- median 12+ months (3 48+)
· GvHD
- "flare up" of GvHD in 3 patients
- no obvious influence on chronic GVHD
Is lack of response to Allo-SCT/DLI due to
inadequate antigen presentation?
· Donor lymphocyte infusions mediate superior graft-
versus-leukemia effects in mixed compared to fully
allogeneic chimeras: a critical role for host antigen-
presenting cells. Sykes. Blood, Aug 2002; 100: 1903 - 1909.
Analysis of longitudinal chimerism in cellular subsets following
nonmyeloablative Allo-SCT
Reinier Raymakers&Harry Dolstra, Nijmegen the Netherlands
T cell chimerism
100%
8356
80%
llse
8349
c
60%
8364
onor
40%
8357
d%
8372
20%
8394
0%
8388
0,5
1
236
9
8376
Follow up (months)
NK cell chimerism
100%
8356
80%
llse
8349
c
60%
8364
or
40%
8357
don%
8372
20%
8394
0%
8388
0,5
1
2
3
6
9
8376
Follow up (months)
Dendritic cell chimerism following NMA
MDC chimerism
100%
8356
80%
llse
8349
60%
rc
8364
no
40%
8357
do%
8372
20%
8394
0%
8388
0,5
1
236
9
8376
Follow up (months)
PDC chimerism
100%
8356
80%
llse
8349
c
60%
8364
40%
8357
donor%
8372
20%
8394
0%
8388
0,5
1
236
9
8376
Follow up (months)
Conclusions and future aspects
·
Induction of (chronic) GvHD seems critical for GvM
- Strategies to stimulate GvHD are not "attractive"
NEW STRATEGIES ARE EXPLORED:
·
Application of "novel" agents (Immune modulation)
- Thalidomide (revlimid)&velcade as maintenance after NMA
Studies are initiated by HOVON/GMMG and IFM
- Combination of low dose DLI + novel agents in relapse (EBMT)
·
Infusion of autologous APC after NMA
- Pre-emptive in case of persistent disease
- Combined with DLI in case of relapse
(Phase 1)studies are initiated (Nijmegen & Utrecht)
Acknowledgments:
Acknowledgements
Nicolaus Kroger
- Hamburg
Jesus F. San Miguel &Jose Perez Simon
- Salamanca
Paolo Corradini
- Milano
Ute Hegenbart & Hartmut Goldschmidt
- Heidelberg
Hermann Einsele
- Wurzburg
Rien van Oers
- Amsterdam
Mark Zijlmans
- Rotterdam
Reinier Raymakers & Harry Dolstra
- Nijmegen
Leo Verdonck & Rob Fijnheer
- Utrecht
Document Outline