bor-sheng ko ( 柯博升 ), m.d. bmt unit and hematology division department of internal medicine...
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Bor-Sheng Ko (柯博升 ), M.D.
BMT Unit and Hematology DivisionDepartment of Internal MedicineNational Taiwan University Hospital
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
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
Graft-versus-Host Disease (GvHD) A major complication after alloHSCT Distinguished from other organ transplantation
Donor Immunity
Recipient Immunity
Graft Rejection GvHD
Pathogenesis
Bone Marrow Transplantation 2008;41:S68-64
Acute vs. Chronic GvHD
Blood 1995;86:3247-56
Artificial Boundary
Acute Chronic
cGVHD in IBMTR:20-30% progressive30-40% interrupted35% de novo
Overlaping syndrome
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
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 !
Skin aGVHD
Dermatology 2008;216:287-304
Colon GvHD
Endoscopy 2005;37:346-50
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
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
Grading of aGvHD
Lancet 2009;373:1550-61
Prognostic Implications of aGvHD
Br J Haematol 1997;96:855-64
IBMTR results
For aGvHD:
Prevention is BETTER than Treatment !!
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 ……………………………………….
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)
Prevention of aGvHD (2)
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
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
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
Cutaneous cGvHD
Dermatology 2008;216:287-304
cGvHD in Lung: Brochiolitis Obliterans (BO) and Organizing Pneumonia (OP)
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
NIH Classification System for cGvHD
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
Prevention and Therapy for cGvHD No effective prophylatic regimens
Therapy: First line: CsA + Corticosteroid
Salvage regimens: Variable
Salvage Therapy for cGvHD (1)
Lancet 2009;373:1550-61
Salvage Therapy for cGvHD (2)
Lancet 2009;373:1550-61
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
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
T-cell Depletion and Relapse
Blood 1991;78:2120-30
Early Leukemia Advanced Leukemia
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)
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
GvHD and Relapse: Evidences of GvT
Blood 1989;73:1720-8
N=154, Relapsed ALL/AML
N=123, CML, CP N=45, CML, AP/ABC
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
Direct Evidences of GvT
Blood 1997;90:4206-11
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
Effects of Pre-DLI Status on Response: CML
Chap.28Hematopoietic Stem Cell Transplantation
CML in A.Molecular relapseB.Cytogenetic relapseC.Chronic phaseD.Accelerated phaseE.Blastic phase
Effects of Disease Types on DLI Response
EBMT data 1997
Strategies to Modify DLI
Chap.28Hematopoietic Stem Cell Transplantation
Pre-emptive DLI
High-risk AMLGvHD(-) on D+120
J Clin Oncol 2005;23:5675-87
Schemes of Non-myeloablative HSCT
New Engl J Med 2006;27:1813-26Hematology 2001:375
Renal Cell Carcinoma with NM-HSCT
New Engl J Med 2000;343:750-8
Thanks for Your Attention
Questions and Discussion…..
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