Extracorporeal photopheresis (ECP) is the first FDA approved cellular photoimmunotherapy for cancer and has demonstrated efficacy in T-cell mediated disorders including prevention and treatment of acute and chronic graft-versus-host disease, organ transplant rejection, scleroderma, Crohn's disease and diabetes mellitus. Due to its exceptional safety profile ECP has gained wide international acceptance through the efforts of leading clinical investigators. Exciting preclinical data and clinical observations provide insight into the mechanisms of action of ECP and are the basis for further clinical investigations.

Univ. Prof. Dr. Hildegard T. Greinix, Prof. Dr. Robert Knobler, both Medical University of Vienna Departments of Internal Medicine I and Dermatology Vienna, Austria.

1;1 History of Extracorporeal Photopheresis;14 1.1;1.1 First Clinical Studies Using ECP;14 1.2;1.2 ECP for Treatment of CTCL and Other Diseases;15 1.3;1.3 Technical Developments in Use of ECP;15 1.4;1.4 Current Role of ECP;17 2;2 Technical Aspects;20 2.1;2.1 ECP in Children and Adolescents;20 2.1.1;2.1.1 Introduction;20 2.1.2;2.1.2 ECP Methodology and Instrumentation;21 2.1.3;2.1.3 Summary;32 2.2;2.2 ECP in Patients with Bleeding Risks;34 2.2.1;2.2.1 Anticoagulation with Heparin;34 2.2.2;2.2.2 Anticoagulation with Acid Citrate Dextrose;36 2.2.3;2.2.3 Anticoagulation during ECP in Patients with Bleeding Risks;37 2.2.4;2.2.4 Anticoagulation during ECP in Patients with Absolute Contraindications for Heparin Use;38 2.2.5;2.2.5 Vienna Experience on ECP with ACD-A;38 2.2.6;2.2.6 Recommendations and Conclusions;40 2.3;2.3 ECP with Central Venous Access;42 2.3.1;2.3.1 Arteriovenous Fistulas (AVFs) or Arteriovenous Grafts (AVGs);42 2.3.2;2.3.2 Central Venous Catheters (CVCs);43 2.3.3;2.3.3 Totally Implantable Central Venous Access Systems (Ports);45 2.3.4;2.3.4 Summary/Conclusions;47 2.4;2.4 New Technical Developments;50 2.4.1;2.4.1 Extracorporeal Photopheresis Regulatory Recommendations;50 2.4.2;2.4.2 The Closed System's New Technical Developments;51 2.4.3;2.4.3 Conclusions;57 3;3 Mechanisms of Action of ECP;60 3.1;3.1 Preclinical GVHD Model;60 3.1.1;3.1.1 Introduction;60 3.1.2;3.1.2 Results;60 3.1.3;3.1.3 Discussion;65 3.2;3.2 Preclinical Hypersensitivity Models;71 3.2.1;3.2.1 Introduction;71 3.2.2;3.2.2 The Experimental Model;71 3.2.3;3.2.3 Characterization of ECP/PUVA-Induced Treg;72 3.2.4;3.2.4 Interleukin-10 is a Crucial Mediator;72 3.2.5;3.2.5 Other Models and Data Indicating a Role of Treg in ECP;74 3.2.6;3.2.6 Conclusion;74 3.3;3.3 Mechanism of Action of ECP - Clinical Evidence;77 3.3.1;3.3.1 Introduction;77 3.3.2;3.3.2 Cellular Vaccination Hypothesis;77 3.3.3;3.3.3 Apoptosis of ECP-Treated Lymphocytes;78 3.3.4;3.3.4 Direct Effect of ECP on Effector Cells;79 3.3.5;3.3.5 ECP Modulation of Peripheral Blood Monocytes and Dendritic Cells;81 3.3.6;3.3.6 Distal Effects on Untreated Lymphocytes in GVHD;82 3.3.7;3.3.7 Emergence of Regulatory T cell Populations during ECP Treatment;84 3.3.8;3.3.8 Dysregulation of B Cell Homeostasis and Hallmarks of Improvement in ECP Treatment in GVHD;85 4;4 Extracorporeal Photopheresis in Acute Graft-versus-Host Disease;96 4.1;4.1 First-Line Therapy of Acute GVHD;96 4.1.1;4.1.1 When to Start First-Line Therapy;96 4.1.2;4.1.2 What First-Line Therapy to Use;96 4.1.3;4.1.3 Duration of First-Line Therapy and Response;97 4.1.4;4.1.4 Combination First-Line Therapy;97 4.2;4.2 Predicing GVHD Severity;98 4.3;4.3 Second-line Therapy of Corticosteroid-Refractory Acute GVHD;98 4.3.1;4.3.1 Defining Steroid-Refractory Acute GVHD;98 4.3.2;4.3.2 Second-Line Therapy with Immunosuppressive Agents;98 4.3.3;4.3.3 ECP in Corticosteroid-Refractory Acute GVHD;99 4.4;4.4 Conclusions on the Use of ECP in Acute GVHD;105 5;5 Extracorporeal Photopheresis in Chronic Graft-versus-Host Disease;110 5.1;5.1 Results of ECP in Cutaneous Manifestations of Chronic GVHD;110 5.1.1;5.1.1 Cutaneous Manifestations of Chronic GVHD;110 5.1.2;5.1.2 Results of Phase II Studies with Non-ECP Therapies for Cutaneous Chronic GVHD;111 5.1.3;5.1.3 Results of Phase II Studies with ECP Treatment for Cutaneous Chronic GVHD;111 5.1.4;5.1.4 Results of Two Phase II Randomized, Single-Blind, Multicenter Studies of ECP for Treatment of Cutaneous Chronic GVHD;112 5.1.5;5.1.5 Summary;116 5.2;5.2 Results of ECP in Extracutaneous Manifestations of Chronic GVHD;119 5.2.1;5.2.1 Introduction;119 5.2.2;5.2.2 Liver and Gastrointestinal (GI) GVHD;119 5.2.3;5.2.3 Ocular and Oral GVHD;123 5.2.4;5.2.4 Chronic GVHD of the Lungs;126 5.2.5;5.2.5 Summary;128 5.3;5.3 ECP in Chronic GVHD: Steroid-Sparing Effect;134 5.3.1;5.3.1 Introduction;134 5.3.2;5.3.2 Corticosteroids and Other Immunosuppressive Agents in Chronic GVHD;134 5.3.3;5.3.3 Overview of ECP in Chronic GVHD and its St