PowerPoint プレゼンテーション

2nd International Conference on Hematology & Blood Disorders（Sep. 29-Oct. 01, 2014 Baltimore, USA）
Graft-versus-GVHD, a second transplantation from another
donor for the rescue from refractory acute GVHD
Hyogo College of Medicine
Kazuhiro Ikegame
Concept of Graft-versus-GVHD (GvGVHD)
Autoimmune
GVHD
joint
skin
Self-reactive
lymphocytes
Donor
lymphocyte
Graft-versus-Autoimmunity
(GVA)
muscle
liver
Graft-versus-GVHD
(GvGVHD)
nerve
gut
DNA
alloreactive
cell therapy
Autologous PBSCT for severe GVHD
mPSL
tacrolimus
MMF
ATG MTX
hemorrhagic cystitis
FLU+CY+TBI
WBC(x106/l)
diarrhea
Plts(x106/l)
skin rash
alloBMT
autoPBSCT
WBC
104
20
ALG 8mg/kg
15
103
TBI 2Gy
102
10
TT 10mg/kg
Plts
10
5
0
20
40
60
80
100
Days after transplantation
Taniguchi Y, et al. Haematologica. 2003; 88.
BM relapse on day 144 after 2nd autoPBSCT
Case reports of autologous PBSCT
for GVHD
Bone Marrow Transplantation (2004) 34, 995–998
AutoSCT for GVHD (mouse model)
1st BMT ( b / d )
2nd BMT ( b / k )
( BDF1)
(B6C3F1)
BM 1×107
spleen 3×107
BM 1×107
spleen 3×107
2weeks
Recipient ( b / k ）
( B6C3F1)
TBI 8.5Gy
Taniguchi Y, et al. Exp Hematol. 2008; 36:1216.
TBI 0, 2, 3, 4, 5 Gy
B6C3F1→(B6C3F1→B6C3F1)
B6C3F1→(BDF1→B6C3F1)
TBI 4Gy
B6C3F1→(BDF1→B6C3F1)
TBI 5Gy TBI toxicity
2nd SCT
TBI
BDF1→B6C3F1
GVHD
TBI 3Gy
B6C3F1→(BDF1→B6C3F1)
TBI 3Gy GVHD
BDF1→B6C3F1
GVHD
BDF1→B6C3F1
BDF1→B6C3F1
TBI 3Gy
B6C3F1→(BDF1→B6C3F1)
TBI 3Gy
B6C3F1→(BDF1→B6C3F1)
TBI 4Gy
B6C3F1→(B6C3F1→B6C3F1)
Problems of AutoSCT for GVHD
1) Difficult to engraft（GVH clones are rejecting clones）
2) Risk of relapse（Loss of GVL effect）
Rejection
BDF1 (b/d)
lymphocytes
b
d
GVL
b
b
k
k
b
No GVL
d
d
k
b
b
d
B6C3F1 (b/k)
stem cells
k
b
B6C3F1 (b/k)
leukemic cells
b
k
GVHD
k
B6C3F1 (b/k)
b normal tissue
b
B6C3F1 (b/k)
leukemic cells
Allogeneic is better than autologous
for severe GVHD?
第17回クリニカルヘマトオンコロジー 5/14/2010
AlloSCT for GVHD (mouse model)
1st BMT ( b / d )
2nd BMT ( b / s )
( BDF1)
(B6B10F1)
BM 1×107
spleen 3×107
BM 1×107
spleen 3×107
1, 2, 3 weeks
Recipient ( b / k ）
( B6C3F1)
TBI 8.5Gy
TBI 0, 2, 3, 4, 5 Gy
T cell chimerism of 1st and 2nd donors after 2nd SCT
Experiment
1
SCT sequence
B6C3F1 → (BDF1→B6C3F1)
b/k
b/d
2nd donor
chimerism
TBI dose
For 2nd SCT
Day 7
3Gy
47 ± 20
95 ± 3.4
± +
Day 14
Improvement in
GVHD score
b/k
2
B6C3F1 → (BDF1→B6C3F1)
4Gy
99 ± 0.8
99 ± 1.1
+
3
B6B10F1 → (BDF1→B6C3F1)
3Gy
99 ± 0.9
99 ± 1.1
+
0
25 ± 10
18 ± 18
-
3Gy
2.6 ± 2.5
1.8 ± 3.6
-
b/k
b/s
4
6
C3DF1
d/k
DBA/2
d/d
7
b/d
b/k
b/k
B6B10F1 → (BDF1→B6C3F1)
b/s
5
b/d
DBA/2
d/d
b/d
b/k
→ (BDF1→B6C3F1)
b/d
b/k
→ (BDF1→B6C3F1)
b/d
0
b/k
→ (BDF1→B6C3F1)
b/d
3Gy is not enough when GVHD clones are rejecting clones
b/k
40 ± 7.1
25 ± 3.1
-
TBI is indispensable in homo-to-hetero (hybrid resistance?)
3Gy
78 ± 8.6
96 ± 2.5
+
Human is more important
than mouse?
Graft-versus-GVHD
Mouse model
Recovery from established graft-vshost disease achieved by bone marrow
transplantation from a third-party
allogeneic donor.
Taniguchi Y, et al. Exp Hematol. 2008.
Clinical
Allogeneic stem cell transplantation
as treatment for heavily treated,
refractory acute graft-versus-host
disease after HLA-mismatched
stem cell transplantation.
Ikegame K, et al. Exp Hematol. 2011.
Second SCT for refractory acute GVHD from another haploidentical donor
(n=15 cases)
Engraftment 11, rejection 4
OS@3yr 53% in engraftment cases, early death of GVHD in all rejected cases
Representative regimen of GvGVHD
day
FLU
30mg/m2
ATGF
2mg/kg
TBI
3Gy
-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4
PBSCT
Tacrolimus civ (9-11ng/ml)
mPSL 1mg/kg
Change of GVHD stage along time course
before and after GvGVHD in engrafted cases
gut
skin
liver
No. 1
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
-10
0
10
20
30
No. 4
No. 5
No. 6
No. 8
No. 9
Patients with complete response (%)
Response and survival after GvGVHD
100
90
engraftment
Engraftment
80
Rejection
70
60
50
40
30
20
rejection
10
0
-10
0
10
20
30
Days after transplantation
engraftment
rejection
40
50
60
Lineup of HCM
(Acknowlegement)
(Coach)
Ward (clinical)
Kaida (FW)
Taniguchi K (FW)
Ishi (FW)
Yoshihara (MF)
Ikegame (MF)
Tamaki (CB)
Inoue
(graduate student)
Kato
(graduate student)
Okada (CB)
Fujioka (SB)
Taniguchi Y (SB)
Nurses
Doctors
Soma (GK)
PT
Lab. (research)
pharmacists
Clinical
psychiatrists
Pain control
team

Download Report