Bor-Sheng Ko ( 柯博升 ), M.D. BMT Unit and Hematology Division Department of Internal Medicine

1. Bor-Sheng Ko (柯博升), M.D. BMT Unit and Hematology Division Department of Internal Medicine National Taiwan University Hospital Prevention and Management of Graft-versus-host Disease (GvHD)and Tumor Relapse移植體抗宿主疾病與腫瘤復發之預防與處置

2. Outlines • GvHD • Definition and Pathogenesis • Acute GVHD (aGvHD) • Clinical spectrum • Prevention and management • Chronic GVHD (cGvHD) • Clinical spectrum • Prevention and Management • Prevention and Management of tumor relapse • Monitoring Relapse • Graft-versus-tumor (GvT) effects • Donor lymphocyte infusion (DLI) and immunotherapy

3. GvHD • Definition and Pathogenesis • Acute GVHD (aGvHD) • Clinical spectrum • Prevention and management • Chronic GVHD (cGvHD) • Clinical spectrum • Prevention and Management • Prevention and Management of tumor relapse • Monitoring Relapse • Graft-versus-tumor (GvT) effects • Donor lymphocyte infusion (DLI) and immunotherapy

4. Graft-versus-Host Disease (GvHD) • A major complication after alloHSCT • Distinguished from other organ transplantation Donor Immunity Recipient Immunity Graft Rejection GvHD

5. Pathogenesis Bone Marrow Transplantation 2008;41:S68-64

6. Acute vs. Chronic GvHD Artificial Boundary Acute Chronic cGVHD in IBMTR: 20-30% progressive 30-40% interrupted 35% de novo Overlaping syndrome Blood 1995;86:3247-56

7. GvHD • Definition and Pathogenesis • Acute GVHD (aGvHD) • Clinical spectrum • Prevention and management • Chronic GVHD (cGvHD) • Clinical spectrum • Prevention and Management • Prevention and Management of tumor relapse • Monitoring Relapse • Graft-versus-tumor (GvT) effects • Donor lymphocyte infusion (DLI) and immunotherapy

8. Clinical Presentations of Acute GvHD (aGvHD) • Started from D+2-5 wk, in 10-90% cases.. • Varied because of risk factors • Target organs • Skin • GI tract: Upper and Lower • Liver: Bile duct epithelium • Immune system • Airways • Vascular endothelium • Tumor cells • Sometimes rapid progression! Potentially fatal !

9. Skin aGVHD Dermatology 2008;216:287-304

10. Colon GvHD Endoscopy 2005;37:346-50

11. Risk Factors for aGvHD • Histoincompatibilities • Patient age/Donor age • Gender mismatch (Female donor to male recipient) • Stem cell sources • Number of transfused cells • Type of prophylatic regimens • Cytokine polymorphism • Conditioning regimens • Donor CMV positivities

12. Diagnosis of aGvHD • Clinical symptoms are not reliable • Too many diagnosis to be differentiated……. • Obtain Pathological diagnosis as possible! • Though histological severity is not correlated well with clinical severity • Clinical judgment with history, clinical signs, laboratory data and pathological diagnosis

13. Grading of aGvHD Lancet 2009;373:1550-61

14. Prognostic Implications of aGvHD IBMTR results Br J Haematol 1997;96:855-64

15. For aGvHD:Prevention is BETTER than Treatment !!

16. Prevention of aGvHD (1) • Donor selection/ Conditioning/ Host factors • In vitro prophylaxis • T-cell depletion.. • In vivo prophylaxis • Anti-T-cell antibodies: • Anti-thymocyte immunoglobulin • Other antibodies • Pharmacological prophylaxis • ……………………………………….

17. Prevention of aGvHD (2) • In vivo prophylaxis • Pharmacological prophylaxis • MTX 15mg/m2 D+1, 10mg/m2 D+3,+6,+11 • Calcineurin inhibitors: CsA, Tacrolimus (FK506) • CsA: serum level 150-400 ng/mL, tapering till D+6m to 12m • Tacrolimus: ≧ CsA, serumlevel below 15 ng/mL • MMF (Mycophenolate mofetil) • In mini-alloHSCT • mTOR inhibitor: sirolimus (rapamycin)

18. Treatment of aGvHD • Gr II-IV aGvHD • First line: Methylprednisolone 2mg/Kg/D for 14 days or more • Steroid non-responsive: Bone Marrow Transplantation 2008;41:S65-70

19. GvHD • Definition and Pathogenesis • Acute GVHD (aGvHD) • Clinical spectrum • Prevention and management • Chronic GVHD (cGvHD) • Clinical spectrum • Prevention and Management • Prevention and Management of tumor relapse • Monitoring Relapse • Graft-versus-tumor (GvT) effects • Donor lymphocyte infusion (DLI) and immunotherapy

20. Clinical Features of cGvHD • 30-50% sibling alloHSCT and 50-70% URD-HSCT • Chronic course, usually not fatal but impaired QOL • More like autoimmune disease • Widespread organ involvement: Blood 2002;100:406-14

21. Cutaneous cGvHD Dermatology 2008;216:287-304

22. cGvHD in Lung: Brochiolitis Obliterans (BO) and Organizing Pneumonia (OP)

23. Classification and Scoring of cGvHD • Seattle classification: • Limited: Only skin or liver • Extensive • NIH-cGvHD Consensus Project Working Gp: • Scoring 0-3 for each organ/system • Mild: 1-2 organ/system with maximum score 1 • Moderate: 3+ organ/system or maximum score 2 • Severe: any organ/system scoring 3 • Lung score: 1= moderate, 2-3=severe Biol Blood Marrow Transplantation 2005;91:945—55

24. NIH Classification System for cGvHD

25. Risk Factors for cGvHD • Stem cell sources • Histocompatibilities • Gender mismatch • T-cell depletion(?) • Ethnicity: Japanese • Donor lymphocyte infusion • aGvHD • Age • High CD34+ cells in alloPBSCT • Tapering of immunosuppresants

26. Prevention and Therapy for cGvHD • No effective prophylatic regimens • Therapy: • First line: CsA + Corticosteroid • Salvage regimens: Variable

27. Salvage Therapy for cGvHD (1) Lancet 2009;373:1550-61

28. Salvage Therapy for cGvHD (2) Lancet 2009;373:1550-61

29. GvHD • Definition and Pathogenesis • Acute GVHD (aGvHD) • Clinical spectrum • Prevention and management • Chronic GVHD (cGvHD) • Clinical spectrum • Prevention and Management • Prevention and Management of tumor relapse • Monitoring Relapse • Graft-versus-tumor (GvT) effects • Donor lymphocyte infusion (DLI) and immunotherapy

30. Tumor Relapse • Major reason of failure in alloHSCT for malignant disease • Most relapsed from recipient cells • Risk factors: • Pre-transplant disease condition • Conditioning Regimens (??) • Immune status: ex., T-cell depletion

31. T-cell Depletion and Relapse Early Leukemia Advanced Leukemia Blood 1991;78:2120-30

32. Monitoring of Leukemia(Tumor) Relapse • Monitor chimerism • Fluorescence in situ hybridization (FiSH) for sex chromosome (1-5%) • Short tandem repeat (STR) (1-10%) • Monitor disease markers: Minimal residual disease (MRD) • Cytogenetics (~5%) • FiSH (1-5%) • Flow cytometry (0.1-0.01%) • Molecular tools (0.1-0.001%) • Reverse transcriptase-polymerise chain reaction (RT-PCR) • Quantitative real-time RT-PCR (QRT-PCR)

33. GvHD • Definition and Pathogenesis • Acute GVHD (aGvHD) • Clinical spectrum • Prevention and management • Chronic GVHD (cGvHD) • Clinical spectrum • Prevention and Management • Prevention and Management of tumor relapse • Monitoring Relapse • Graft-versus-tumor (GvT) effects • Donor lymphocyte infusion (DLI) and immunotherapy

34. GvHD and Relapse: Evidences of GvT N=154, Relapsed ALL/AML N=123, CML, CP N=45, CML, AP/ABC Blood 1989;73:1720-8

35. Donor Lymphocyte Infusion (DLI) • Donor buffy coat infusion • Prepared by leukaphresis, not mobilized with G-CSF • Adoptive cellular immunotherapy • Presented as CD3+T-cell dosage

36. Direct Evidences of GvT Blood 1997;90:4206-11

37. Effects of DLI • Major determinants for treating tumor relapse • CD3+T-cell dosage • Diagnosis • Pre-DLI disease status • Major Complication: GvHD • Seperating GvL from GvHD ?! • Other applications for DLI • Adoptive immunotherapy for viral infections

38. Effects of Pre-DLI Status on Response: CML • CML in • Molecular relapse • Cytogenetic relapse • Chronic phase • Accelerated phase • Blastic phase Chap.28 Hematopoietic Stem Cell Transplantation

39. Effects of Disease Types on DLI Response EBMT data 1997

40. Strategies to Modify DLI Chap.28 Hematopoietic Stem Cell Transplantation

41. Pre-emptive DLI High-risk AML GvHD(-) on D+120 J Clin Oncol 2005;23:5675-87

42. Schemes of Non-myeloablative HSCT New Engl J Med 2006;27:1813-26 Hematology 2001:375

43. Renal Cell Carcinoma with NM-HSCT New Engl J Med 2000;343:750-8

44. Thanks for Your Attention Questions and Discussion…..