慢性移植物抗宿主病.ppt

　　Chronic GVHD: Pathophysiology and Novel Therapeutic Strategies

　　Ting Liu Department of Hematology West China Hospital Sichuan University 2014. 4. Xiamen

　　内 容

　　Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD

　　CIBMTR: GVHD 发病率

　　Ringdén O, et al. Blood. 2009;113:3110-3118.

　　NIH 新的GVHD分类标准(2005)

　　Acute GVHD classic acute GVHD late-onset acute GVHD Chronic GHVD Classic chronic GVHD Overlap syndrome NIH分类标准最重要的变化是以临床表现和器官受累的程度，而不是移植后时间来进行分类，这有利于临床医生作出更符合病理生理学改变的诊断和治疗策略

　　Filipovich AH, et al. Biol. Blood Marrow Transplant. 11(12), 945–956 (2005).

　　GVHD classification after the NIH consensus conference

　　Pavletic S Z , and Fowler D H Hematology 2012;2012:251-264

　　cGVHD发病的危险因素

　　Acute GVHD Older age of recipient and donor Female multiparous donor Mismatched and unrelated donors PBSC product Disease type: CML, Aplastic anemia ↓ High CD34 dose and/or T-cell dose Second transplants DLIs CMV?

　　影响cGVHD发病率的因素

　　Classification Progressive ? poorest prognosis Quiescent de novo #1 risk factor: history of acute GVHD Changing risk factors Older recipient age Donors(unrelated, haploidentic) Non-myeloablative conditioning Peripheral blood stem cell source Donor leukocyte infusions (DLI)

　　Lee et al., Biol Blood Marrow Transplant 2003; 9:215-33.

　　慢性GVHD的临床表现

　　cGVHD: 多形性的皮肤病变

　　Epidermal cGVHD Lichen planus-like Papulosquamous Ichthyosiform Poikiloderma Keratosis pilaris-like Acral erythema Dermal cGVHD Lichen-sclerosus-like Dermal sclerosis Subcutaneous cGVHD Subcutaneous sclerosis Fasciitis

　　cGVHD

　　cGVHD ：口腔黏膜溃疡

　　Treister N et al. Blood 2012;120:3407-3418

　　Pérez-Simón J A et al. Haematologica 2012;97:1187-1195

　　不同类型cGVHD的预后

　　Multivariate risk factor profiles acute GVHD and chronic GVHD

　　Flowers M, et al. Blood.2011;117(11):3214-3219)

　　cGVHD危险度积分*

　　Mild – no significant impairment of function Only 1-2 organs (except lungs) Maximum organ score 1 Moderate – significant impairment but no major disability Three or more organs with max score 1 One organ with max score 2 Lung score of 1 Severe – major disability Score of 3 in any organ or site Lung score of 2

　　*采用危险度积分代替了既往局限性和广泛性的分类

　　OS：根据cGVHD危险度积分

　　Pavletic S Z , and Fowler D H Hematology 2012;2012:251-264

　　内 容

　　Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD

　　cGVHD的病理生理学

　　Thymic damage and defective negative selection Deficiency of T-regs TGF-β and PDGF pathways mediated fibrosis Th1/Th2/Th17 paradigm cytokine Dysregulated B-cell and humoral immunity

　　Takanori Teshima, ASBMT 2008

　　The 5 Tenets of cGVHD

　　中央免疫耐受：胸腺损害学说

　　外周免疫耐受：T-regs细胞缺陷

　　T-regs play a critical role in peripheral tolerance and development of cGVHD CD4+ lymphopenia is a key factor in Treg homeostasis, and impaired reconstitution of Tregs can result in loss of tolerance and development of cGVHD Adoptive transfer of Tregs and regulation to increase Tregs are considered to be e?ective clinical strategies

　　TGF-β 和 PDGF 信号通路与纤维化

　　cGVHD is characterized by ?brostic changes, TGF-β1 levels are increased signi?cantly in the patients TGF-β plays an important role in the generation and maintenance of Tregs PDGF pathway may result in autoimmune e?ects, and stimulatory antibodies to the PDGFR were found in all extensive cGVHD patients Imatinib may inhibit PDGFR, has been investigated for the refractory cGVHD

　　The Th1/Th2/Th17 的发育和平衡

　　Weaver CT. Immunity. 2006;24(6):677-88.

　　The Th1/Th2/Th17 发育和平衡

　　Donor CD4+ T cells can reciprocally di?erentiate into Th1, Th2, and Th17 cells That mediate organ speci?c GVHD (Th1: gut and liver; Th2: lung and skin; Th17: gut and skin) Th1 and Th17 contribute to the development of cGVHD

　　cGVHD：B细胞和体液免疫异常

　　A strong correlation between cGVHD and the presence of antibodies to Y chromosome encoded histocompatibility antigens Elevated B cell-activating factor (BAFF) levels, which promotes survival and di?erentiation of activated B cells, have been observed in patients with cGVHD. Genetic variation in BAFF was also correlated with cGVHD cGVHD was associated with an increased number of B cells expressing high levels of Toll-like receptor 9 In vivo depletion of B cells using rituximab can suppress the progression of complex cGVHD

　　cGVHD Summary

　　(Gp:) Thymus

　　(Gp:) HSC

　　(Gp:) CD8

　　(Gp:) CD4

　　(Gp:) Treg

　　(Gp:) B

　　Inflammatory cytokines

　　Fibrosing cytokines

　　Autoantibody

　　Fibrosis and organ dysfunction

　　Death from infection/organ failure

　　Allo

　　Auto

　　内 容

　　Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD

　　cGVHD的药物预防

　　Seatle group observed extended calcineurin inhibitor (CSA) treatment may decrease chronic GVHD CSA 6 months vs 24 months in patients with prior aGVHD or evidence of subclinical chronic GVHD on skin biopsy = NO EFFECT Thalidomide D+80 HIGHER rate of cGVHD and mortality Steroids until 6 months after transplantation HIGHER than expected incidence of severe cGVHD Hydroxychloroquine+ CSA x 1 yr = NO EFFECT MMF (D150) + CSA (D80)= NO EFFECT Pre-transplant ATG may decrease cGVHD

　　Mangarelli et al. Hematologica. 2003;88:315, Kansu et al. Blood. 2001;98:3868. Chao et al. BBMT. 1996;2:96 Ringden et al. Exp Hem.1985;13:1062 Fong et al. BBMT. 2007;13:1201 Baron et al. BBMT. 2007;13:1041

　　cGVHD：系统治疗指征

　　* Platelets <100,000/microliter or receiving steroids at time of diagnosis of CGVHD ? The benefits of graft-vs.-tumor effect and the risk of CGVHD need to be weighted Filipovic, BBMT 2005; 12: 945-955

　　Steroids: Sullivan et al, Blood 1988; 72. N=164 Pred 1mg/kg vs Pred+Azathioprine NRM 21% vs 41% (p=0.03) Most common cause of death = relapse Steroids + CSA: Koc et al, Blood 2002; 100. N=287 RCT: Pred vs Ped+CSA No difference in TRM, OS, relapse, need for secondary cGVHD Tx Relapse free survival better in prednisone only arm

　　cGVHD: 一线治疗

　　Martin. IntJHem. 2004;79:221 Stewart et al, Blood 2004; 104 Vogelsang. BJH.2004;125:435 Lee, Blood.2005;105

　　Progression on steroids Within 2-3 months if no improvement on steroids Inability to taper steroids without recurrence Inability to tolerate steroids or calcineurin inhibitors (TTP)

　　cGVHD: 二线治疗

　　Steroid pulse CSA Tacro MMF Sirolimus ECP Pentostatin Rituximab Hydroxychloroquine Thalidomide/Revlimid

　　Clofazamine Azathioprine ATG TLI Low dose MTX Dacluzimab Infliximab Etanercept Imatinib Montelukast

　　cGVHD: 二线治疗可选择药物

　　cGVHD：二线治疗的疗效

　　Lee et al, BBMT 2002

　　Response rates in second line therapy

　　Nishimori H, Acta Med Okayama. 2013;67(1):1-8.

　　内 容

　　Update of knowledges in cGVHD Progress in pathobiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD

　　Keratinocyte growth factor (KGF)

　　KGF treatment improves the restoration of thymic DCs and prevents the de novo generation of pathogenic CD4+ T cells causing cGVHD the e?cacy of palifermin treatment for cGVHD has being clinical studies to assess the role of the thymus as a target of cGVHD treatment

　　Zhang Y, J Immunol (2007) 179: 3305-3314.

　　靶向TGF-β / PDGF 信号途径治疗

　　Olivieri A. Blood. 2013;122(25):4111-4118

　　Imatinib was planned for at least 6 months, starting at 100 mg/day during the first 15 days. In the absence of severe (grade 3-4 WHO) toxicity, the dosage was gradually increased to 400 mg/day.

　　Treg therapy: Immunologic effects of 8 weeks of low-dose interleukin-2

　　Koreth et al. N Engl J Med (2011) 365: 2055-2066.

　　Immunologic effects of extended treatment with interleukin-2 on Tregs

　　Koreth et al N Engl J Med (2011) 365: 2055-2066.

　　Retinoids for the Treatment of Chronic GVHD

　　cGVHD

　　Hematology/Oncology

　　Dermatology

　　Dentistry/Oral Surgery

　　Rheumatology

　　Infectious Diseases

　　Ophthalmology

　　Pain/Palliative Care

　　Nutritional Support

　　Rehabilitation Medicine

　　NIH: multidisciplinary approach to cGVHD

　　NIH National Consensus Guidelines for cGVHD Clinical Trials and Management