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…..