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)