2 nd International Conference on Hematology & Blood Disorders ( Sep. 29-Oct. 01, 2014 Baltimore,...
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Transcript of 2 nd International Conference on Hematology & Blood Disorders ( Sep. 29-Oct. 01, 2014 Baltimore,...
2nd International Conference on Hematology & Blood Disorders ( Sep. 29-Oct. 01, 2014 Baltimore, USA )
Hyogo College of Medicine
Graft-versus-GVHD, a second transplantation from another Graft-versus-GVHD, a second transplantation from another donor for the rescue from refractory acute GVHDdonor for the rescue from refractory acute GVHD
Kazuhiro Ikegame
liver
gut
skin
joint
muscle
DNA
Self-reactive lymphocytes
Donor lymphocyte
Autoimmune GVHD
alloreactivecell therapy
nerve
Graft-versus-Autoimmunity(GVA)
Graft-versus-GVHD(GvGVHD)
Concept of Graft-versus-GVHD (GvGVHD)Concept of Graft-versus-GVHD (GvGVHD)
alloBMT
Days after transplantation
0 20 40 60 80 100
10
102
103
104
WBC(x106/l) Plts(x106/l)
5
10
15
20
skin rash
WBC
Plts
MMF
FLU+CY+TBI
ATG MTX
BM relapse on day 144 after 2nd autoPBSCT
ALG 8mg/kg
Autologous PBSCT for severe GVHDAutologous PBSCT for severe GVHD
diarrhea
hemorrhagic cystitis
mPSL
TBI 2Gy
TT 10mg/kg
autoPBSCTautoPBSCT
tacrolimus
Taniguchi Y, et al. Haematologica. 2003; 88.
Bone Marrow Transplantation (2004) 34, 995–998
Case reports of autologous PBSCT Case reports of autologous PBSCT for GVHDfor GVHD
1st BMT ( b / d ) 2nd BMT ( b / k )
2weeks
BM 1×107
spleen 3×107
Recipient ( b / k )
TBI 8.5Gy( B6C3F1)
( BDF1) (B6C3F1)
TBI 0, 2, 3, 4, 5 Gy
BM 1×107
spleen 3×107
AutoSCTAutoSCT for GVHD (mouse model)for GVHD (mouse model)
Taniguchi Y, et al. Exp Hematol. 2008; 36:1216.
2nd SCT
B6C3F1→(B6C3F1→B6C3F1)
B6C3F1→(BDF1→B6C3F1)TBI 4Gy
B6C3F1→(BDF1→B6C3F1)TBI 5GyTBI toxicity
BDF1→B6C3F1TBI 3Gy
BDF1→B6C3F1GVHD
GVHD
B6C3F1→(BDF1→B6C3F1)TBI 3GyTBI
BDF1→B6C3F1
BDF1→B6C3F1TBI 3Gy
B6C3F1→(BDF1→B6C3F1)TBI 3Gy
B6C3F1→(BDF1→B6C3F1)TBI 4Gy
B6C3F1→(B6C3F1→B6C3F1)
GVHD
Problems of AutoSCT for GVHDProblems of AutoSCT for GVHD
1) Difficult to engraft ( GVH clones are rejecting clones )
2) Risk of relapse ( Loss of GVL effect )
B6C3F1 (b/k)normal tissue
B6C3F1 (b/k)stem cells
B6C3F1 (b/k)leukemic cells B6C3F1 (b/k)
leukemic cells
BDF1 (b/d)lymphocytes
k
k
kk
k
k
b
b
b
b
bb
b b
b
b
dd
d
d
GVLGVL
GVHDGVHD
RejectionRejection
No GVLNo GVL
第 17 回クリニカルヘマトオンコロジー 5/14/2010
Allogeneic is better than autologousAllogeneic is better than autologousfor severe GVHD?for severe GVHD?
1st BMT ( b / d ) 2nd BMT ( b / s )
1, 2, 3 weeks
BM 1×107
spleen 3×107
Recipient ( b / k )
TBI 8.5Gy( B6C3F1)
( BDF1) (B6B10F1)
TBI 0, 2, 3, 4, 5 Gy
BM 1×107
spleen 3×107
AlloSCTAlloSCT for GVHD (mouse model)for GVHD (mouse model)
Experiment
1
2
3
4
5
6
7
SCT sequence
TBI doseFor 2nd SCT Day 7 Day 14
Improvement inGVHD score
3Gy
4Gy
3Gy
0
3Gy
0
3Gy
47 ± 20
99 ± 0.8
99 ± 0.9
25 ± 10
2.6 ± 2.5
40 ± 7.1
78 ± 8.6
95 ± 3.4
99 ± 1.1
99 ± 1.1
18 ± 18
1.8 ± 3.6
25 ± 3.1
96 ± 2.5
+
+
+
-
-
-
+
T cell chimerism of 1T cell chimerism of 1stst and 2 and 2ndnd donors after 2 donors after 2ndnd SCT SCT
3Gy is not enough when GVHD clones are rejecting clones
TBI is indispensable in homo-to-hetero (hybrid resistance?)
B6C3F1 → (BDF1→B6C3F1)
B6C3F1 → (BDF1→B6C3F1)
B6B10F1 → (BDF1→B6C3F1)
B6B10F1 → (BDF1→B6C3F1)
C3DF1 → (BDF1→B6C3F1)
DBA/2 → (BDF1→B6C3F1)
DBA/2 → (BDF1→B6C3F1)
±b/k b/d b/k
b/k b/d b/k
b/s b/d b/k
b/s b/d b/k
d/k b/d b/k
d/d b/d b/k
d/d b/d b/k
2nd donorchimerism
Human is more importantHuman is more importantthan mouse?than mouse?
Recovery from established graft-vs-host disease achieved by bone marrow transplantation from a third-party allogeneic donor.Taniguchi Y, et al. Exp Hematol. 2008.
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
Mouse modelMouse model ClinicalClinical
Graft-versus-GVHDGraft-versus-GVHD
-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4
FLU 30mg/m2
ATGF 2mg/kg
day
Tacrolimus civ (9-11ng/ml)
mPSL 1mg/kg
PBSCT
TBI 3Gy
Representative regimen of GvGVHDRepresentative regimen of GvGVHD
skin
0 10 20 30-10 0 10 20 30-10
gut
0 10 20 30-10
liver
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
10 20 30 10 20 30 0 10 20 30-10
No. 1
No. 4
No. 5
No. 6
No. 8
No. 9
Change of GVHD stage along time course Change of GVHD stage along time course before and after GvGVHD in engrafted casesbefore and after GvGVHD in engrafted cases
0-100-10
0
10
20
30
40
50
60
70
80
90
100
-10 0 10 20 30 40 50 60
Days after transplantation
Engraftment
RejectionP
atie
nts
wit
h co
mpl
ete
resp
onse
(%
)
Response and survival after GvGVHDResponse and survival after GvGVHD
engraftment
rejection
engraftment
rejection
Fujioka (SB)
Okada (CB)
Taniguchi K (FW)
Ikegame (MF)
Inoue (graduate student)
Lineup of HCM(Acknowlegement)
Ward (clinical)
Lab. (research)
(Coach)
Kato (graduate student)
Soma (GK)
Ishi (FW)
Kaida (FW)
Yoshihara (MF)
Taniguchi Y (SB)
Nurses Doctors
Pain controlteam
Clinicalpsychiatrists
pharmacists
PT
Tamaki (CB)