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Hyogo College of Medicine

2 nd 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. The Hospital of Hyogo College of Medicine. Hyogo College of Medicine.

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Hyogo College of Medicine

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  1. 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 The Hospital of Hyogo College of Medicine Hyogo College of Medicine Kazuhiro Ikegame

  2. Concept of Graft-versus-GVHD (GvGVHD) Autoimmune GVHD joint skin Self-reactive lymphocytes Donor lymphocyte Graft-versus-Autoimmunity (GVA) liver muscle Graft-versus-GVHD (GvGVHD) nerve gut alloreactive cell therapy DNA

  3. Autologous PBSCT for severe GVHD mPSL tacrolimus MMF ATG MTX hemorrhagic cystitis FLU+CY+TBI diarrhea Plts(x106/l) WBC(x106/l) skin rash alloBMT autoPBSCT WBC 20 104 ALG 8mg/kg 15 103 TBI 2Gy 10 TT 10mg/kg 102 Plts 10 5 0 20 40 60 80 100 Days after transplantation BM relapse on day 144 after 2nd autoPBSCT Taniguchi Y, et al. Haematologica. 2003; 88.

  4. Case reports of autologous PBSCT for GVHD Bone Marrow Transplantation (2004) 34, 995–998

  5. AutoSCTfor 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 0, 2, 3, 4, 5 Gy TBI 8.5Gy Taniguchi Y, et al. Exp Hematol. 2008; 36:1216.

  6. B6C3F1→(B6C3F1→B6C3F1) B6C3F1→(BDF1→B6C3F1) TBI 4Gy BDF1→B6C3F1 TBI 3Gy B6C3F1→(BDF1→B6C3F1) TBI 5Gy GVHD TBI toxicity GVHD BDF1→B6C3F1 2nd SCT B6C3F1→(BDF1→B6C3F1) TBI 3Gy GVHD TBI BDF1→B6C3F1 BDF1→B6C3F1 TBI 3Gy B6C3F1→(BDF1→B6C3F1) TBI 3Gy B6C3F1→(BDF1→B6C3F1) TBI 4Gy B6C3F1→(B6C3F1→B6C3F1)

  7. 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 k b b k b d GVL No GVL d d B6C3F1 (b/k) stem cells b k b d k b k b B6C3F1 (b/k) normal tissue b B6C3F1 (b/k) leukemic cells GVHD k b B6C3F1 (b/k) leukemic cells

  8. 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

  9. AlloSCTfor 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

  10. T cell chimerism of 1st and 2nd donors after 2nd SCT 2nd donor chimerism TBI dose For 2nd SCT Improvement in GVHD score Experiment SCT sequence Day 7 Day 14 1 3Gy 47 ± 20 95 ± 3.4 + B6C3F1 → (BDF1→B6C3F1) ± b/k b/d b/k 2 B6C3F1 → (BDF1→B6C3F1) 4Gy 99 ± 0.8 99 ± 1.1 + b/k b/d b/k 3 B6B10F1 → (BDF1→B6C3F1) 3Gy 99 ± 0.9 99 ± 1.1 + b/s b/d b/k 4 B6B10F1 → (BDF1→B6C3F1) 0 25 ± 10 18 ± 18 - b/s b/d b/k 5 3Gy 2.6 ± 2.5 1.8 ± 3.6 - C3DF1 → (BDF1→B6C3F1) d/k b/d b/k 3Gy is not enough when GVHD clones are rejecting clones 6 DBA/2 → (BDF1→B6C3F1) 0 40 ± 7.1 25 ± 3.1 - d/d b/d b/k TBI is indispensable in homo-to-hetero(hybrid resistance?) 7 DBA/2 → (BDF1→B6C3F1) 3Gy 78 ± 8.6 96 ± 2.5 + d/d b/d b/k

  11. Human is more important than mouse?

  12. Graft-versus-GVHD Mouse model Clinical 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

  13. Representative regimen of GvGVHD day -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 PBSCT FLU 30mg/m2 ATGF 2mg/kg TBI 3Gy Tacrolimus civ (9-11ng/ml) mPSL 1mg/kg

  14. Change of GVHD stage along time course before and after GvGVHD in engrafted cases gut skin liver No. 1 0 -10 10 20 30 -10 0 10 20 30 -10 0 10 20 30 No. 4 0 0 -10 0 10 20 30 -10 10 20 30 -10 10 20 30 No. 5 0 0 0 -10 10 20 30 -10 10 20 30 -10 10 20 30 No. 6 0 0 0 -10 10 20 30 -10 10 20 30 -10 10 20 30 No. 8 0 0 0 -10 10 20 30 -10 10 20 30 -10 10 20 30 No. 9 -10 0 10 20 30 -10 0 10 20 30 -10 0 10 20 30

  15. Response and survival after GvGVHD engraftment Patients with complete response (%) rejection engraftment rejection

  16. Lineup of HCM(Acknowlegement) Comedical staffs of the ward (Coach) team effort Ward (clinical) Prof. Ogawa Nurses Doctors Kaida (FW) Taniguchi K (FW) Ishi (FW) Inoue (graduate student) Yoshihara (MF) Kato (graduate student) Ikegame (MF) PT Okada (CB) Tamaki (CB) pharmacists Fujioka (SB) Taniguchi Y (SB) Pain control team Clinical psychiatrists Soma (GK) Lab. (research)

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