The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies

Preface Contents Editors and Contributors About the Editors Contributors Abbreviations Part I: Introduction Topic Leaders: Anna Sureda and Jane Apperley 1: HCT: Historical Perspective 1.1 Introduction 1.2 Early Enthusiasm and Disappointment 1.3 Back to the Laboratory: Focus on Animal Studies 1.4 Resuming Clinical Transplantation: 1968–1980s 1.5 Moving Ahead: The 1990s and Beyond References 2: The EBMT: History, Present, and Future 2.1 Introduction 2.2 The Past: Development of HCT and EBMT 2.3 The Present 2.4 The Future References 3: Registries: A Bridge Between Donor and Recipient 3.1 Introduction 3.1.1 What Is a Registry? 3.1.2 What Is WMDA? 3.2 The Role of the Registry: Patient Perspective 3.2.1 Find the Best Suitable Graft: Search and Match Service 3.2.2 Back-Up Donor Strategy 3.2.3 Registries as Partners of Transplant Centres 3.3 The Role of a Registry: Donor Perspective 3.3.1 Donor Recruitment 3.3.2 Donor Pool HLA Diversity 3.3.3 Donor Profile: Young, Healthy and High-Resolution Typed 3.3.4 Donor Availability: Focus of Registries Worldwide 3.4 Working Together to Deliver Best Care to Patient and Donor 3.4.1 Backup Donor 3.4.2 Serious (Product) Events and Adverse Reactions (SPEAR) 3.4.3 Donor Follow-Up 3.4.4 Patient Follow-Up 3.4.5 Addressing Crisis Situations 3.4.6 Donor-Patient Contact 3.4.7 Related Donor 3.4.8 Research 3.5 Future of Registries References 4: The HCT Unit 4.1 Introduction 4.2 Inpatient Unit 4.3 Ancillary Medical Services 4.4 Outpatient Unit 4.5 Blood Bank 4.6 Laboratory 4.7 HLA Typing Lab 4.8 Stem Cell Collection 4.9 Stem Cell Processing Facility 4.10 Radiology 4.11 Pharmacy 4.12 Staffing and Human Resources 4.13 Chimeric Antigen Receptor T-Cell (CAR-T Cell) Unit 4.14 Institutional Database and Data Manager 4.15 Quality Control 4.16 Transplant Coordinator Further Reading 5: JACIE Accreditation of HCT Programs 5.1 Introduction 5.2 Background 5.3 Impact of Accreditation in Clinical Practice 5.4 JACIE-FACT Accreditation System 5.5 Benchmarking 5.6 Activity of JACIE, Including Impact of Pandemic References 6: Statistical Methods in HCT and Cellular Therapies 6.1 Introduction 6.2 Endpoints 6.3 Analysis of Time-to-Event Outcomes 6.3.1 Kaplan-Meier Curves 6.3.2 Cumulative Incidence Curves 6.3.3 Comparison of Groups 6.3.4 Proportional Hazard Regression Analysis 6.4 Advanced Methods 6.4.1 Multi-State Models 6.4.2 Random Effect Models 6.4.3 Long-Term Outcomes: Relative Survival/Cure Models 6.4.4 Propensity Scores 6.4.5 Methods for Missing Values References Part II: Biological Aspects Topic Leaders: Chiara Bonini, Raffaella Greco and Jürgen Kuball 7: Biological Properties of Hematopoietic Stem Cells: Scientific Basis for Hematopoietic Cell Transplantation 7.1 Introduction 7.2 Self-Renewal 7.3 Commitment and Differentiation: New Data Challenge the Historical View of Hematopoietic Hierarchy 7.4 The Bone Marrow Niches and Maintenance of Stemness 7.5 Preclinical Models of HCT 7.6 Gene Transfer/Gene Editing/Gene Therapy (GT) Targeting HSCs 7.7 Studying the Dynamics of Hematopoietic Reconstitution Upon HCT 7.8 From Experimental Hematology to Medical Practices and Hematopoietic Cellular Therapies References 8: Biological Properties of Cells Other Than HSCs 8.1 Introduction 8.2 Conventional or Alpha Beta T Cells 8.3 Unconventional T Cells 8.4 NK Cells 8.5 Mesenchymal Stromal Cells References 9: Histocompatibility 9.1 Introduction 9.2 The Biology of Histocompatibility 9.2.1 Major Histocompatibility Antigens 9.2.2 Structure and Function of HLA Class I and II Molecules 9.2.3 HLA Polymorphism and Tissue Typing 9.2.4 T-Cell Alloreactivity 9.3 HLA Matching in Allo-HCT 9.3.1 Donor Types 9.3.2 HLA Matching in Unrelated HCT 9.3.2.1 Matched UDs 9.3.2.2 Mismatched UDs 9.3.3 HLA Matching in Haploidentical HCT 9.3.4 HLA Matching in Unrelated Cord Blood HCT 9.3.5 Models of High-Risk/Nonpermissive HLA Mismatches 9.3.6 Factors Influencing the Role of Histocompatibility 9.3.7 Guidelines for UD Selection by Histocompatibility 9.4 Non-HLA Immunogenetic Factors 9.4.1 An Overview 9.4.2 Clinical Impact of Non-HLA Immunogenetic Factors References 10: Clinical and Biological Concepts for Mastering Immune Reconstitution After Hematopoietic Cell Transplantation: Toward Practical Guidelines and Greater Harmonization 10.1 Introduction/Background 10.1.1 Impact of Conditioning Regimens on Immune Reconstitution and Outcomes: Pharmacokinetics–Pharmacodynamics (PK–PD) and Individualized Dosing 10.2 Graft Composition as an Additional Predictor of Immune Reconstitution and Clinical Outcomes 10.2.1 Monitoring: Immune Cell Phenotyping 10.2.2 Immune Monitoring: Secretome Analyses 10.2.3 Immune Monitoring of Virus-Specific T-Cell Responses 10.3 From Transplantation to Immune Monitoring of CAR T Cells, Harmonization Is Needed 10.4 In Summary References Part III: Methodology and Clinical Aspects Topic Leaders: Nicolaus Kröger, Arnon Nagler, Enric Carreras and Selim Corbacioglu 11: Evaluation and Counseling of Candidates 11.1 Evaluation of Candidates and Risk Factors for HCT 11.1.1 Introduction 11.1.2 Candidates’ Evaluation Workflow 11.1.2.1 The First Visit 11.1.2.2 Pre-Apheresis Visit 11.1.2.3 The Last Visit Before Admission 11.1.2.4 Medical History 11.1.2.5 Information to Provide (See Detailed Information in the Counseling Section) 11.1.3 Pretransplant Evaluation 11.1.4 Risk Assessment 11.1.4.1 Individual Risk Factors 11.1.4.2 Predictive Models The Disease Risk Index (DRI) The EBMT Risk Score (Gratwohl et al. 1998, 2009) HCT-Specific Comorbidity Index (HCT-CI) (Sorror et al. 2005) The EBMT Machine Learning Algorithm (Shouval et al. 2015) The Myelofibrosis Transplant Scoring System (MTSS) Score for Myelofibrosis 11.1.4.3 The Predictive Capacity of these Models 11.1.5 Practical Applications of Risk Assessment 11.2 Counseling of Candidates 11.2.1 Introduction 11.2.2 Understanding the Benefits and Risks of Allogeneic Transplantations 11.2.3 Understanding the Transplant Procedure: The Donor, the Conditioning Regimen, and the Clinical Complications 11.2.4 Posttransplant Treatment Options 11.2.5 Alternative Treatment Options to Autologous and Allogeneic Transplantation 11.2.6 Logistics References 12: Donor Selection for Adults and Pediatrics 12.1 Introduction 12.2 Donor Human Leukocyte Antigen (HLA) Compatibility (See Chap. 9) 12.3 Donor Selection for Adult Patients 12.3.1 Donor Type 12.3.1.1 Matched Related Siblings and Unrelated Donors (URDs) 12.3.1.2 Haploidentical Related Donors 12.3.2 The Role of Non-HLA Donor Characteristics 12.3.3 Donor Choice According to Stem Cell Source 12.3.4 Anti-HLA Antibodies 12.4 Donor Selection for Pediatric Patients 12.4.1 Pediatric Recipient Size 12.4.2 Indications 12.4.3 Donor Type 12.4.4 Haploidentical Donors in Pediatrics 12.4.5 Stem Cell Source 12.4.6 Other Donor–Recipient-Related Factors References 13: Conditioning 13.1 An Overview 13.2 Total Body Irradiation 13.3 Myeloablative Non-TBI-Containing Conditioning 13.4 Non-Myeloablative, Reduced Intensity and Reduced Toxicity Conditioning 13.5 Conditioning Regimens for Allo-HCT from Alternative Donors: Mismatched Unrelated Donor (MMUD), CB, and Haploidentical 13.6 Preparative Conditioning for Autologous HCT References 14: Selection of Stem Cell Source 14.1 Introduction 14.2 Factors Influencing the Selection of the Source 14.2.1 Bone Marrow 14.2.2 Peripheral Blood 14.2.3 Cord Blood 14.2.3.1 Disease-Related Considerations 14.3 Differences in the Composition of BM vs. PB 14.4 Main Results of Studies Comparing BM and PB 14.5 The Role of Cord Blood References 15: Bone Marrow Harvesting for HCT 15.1 Introduction 15.2 Advantages and Disadvantages of BM 15.3 The Technique of BM Collection 15.4 In-House Collection Kits 15.5 Major and Minor Complications According to the NMDP (Pulsipher et al. 2014) 15.6 Other Therapeutic Applications of BM Harvesting 15.6.1 Culture-Adapted Mesenchymal Stromal Cells (MSCs) References 16: Mobilization and Collection of HSC 16.1 Introduction 16.2 Strategies of Autologous Stem Cell Mobilization 16.2.1 Mobilization Without Chemotherapy (“Steady State”) 16.2.2 Mobilization with Chemotherapy 16.3 CD34+ Cell Count and Timing of Leukapheresis 16.4 Target HSC Collection Count 16.4.1 Cell Target for Autologous Transplantation 16.4.2 Cell Target for Allogeneic Transplantation 16.5 Leukapheresis 16.6 Management of Poor Mobilizers 16.6.1 Mobilization Failure Among Patients (Autologous SCT) 16.6.2 Mobilization Failure in Allogeneic HSC Donors 16.7 Future Directions References 17: Mobilization and Collection of HSCs in Children 17.1 Introduction 17.2 Patient Selection and Pre-Procedure Preparation 17.2.1 Patient Selection and Testing 17.2.2 Bone Marrow (BM) vs. Peripheral Blood Stem Cells (PBSCs) and Risk Analysis 17.2.3 Children as Allogeneic Donors 17.3 Bone Marrow Harvesting 17.4 Peripheral Blood Stem Cell Harvesting 17.4.1 Mobilization and Preparation 17.4.2 Vascular Access 17.4.3 Apheresis Techniques 17.4.4 Apheresis Monitoring References 18: Procurement and Management of Cord Blood Unit for Allogeneic Transplantation 18.1 Introduction 18.2 Collection 18.3 Processing and Banking 18.3.1 UCB Cell Processing 18.3.2 Testing and Quality Assessment 18.3.2.1 Safety 18.3.2.2 Identity 18.3.2.3 Purity 18.3.2.4 Potency 18.4 Selecting CBU for Transplantation References 19: Graft Manipulation 19.1 Introduction 19.2 Graft Manipulation 19.2.1 Physical Manipulations 19.2.1.1 Volume Reduction 19.2.1.2 Washing to Reduce Plasma Antibodies or Anticoagulants 19.2.1.3 Depletion of Erythrocytes 19.2.2 Immunomagnetic Procedures 19.2.2.1 CD34 Enrichment 19.2.2.2 CD133 Enrichment 19.2.2.3 T-Cell Depletion CD3 Depletion TcRαβ Depletion CD19 Depletion Stem Cell Boosts 19.2.3 Add Back of Donor T-Cells 19.2.3.1 Unmanipulated T-Cells 19.2.3.2 CD45RA Depletion 19.2.3.3 Regulatory and Conventional T-Cells 19.2.3.4 Virus-Specific T-Cells 19.3 Regulatory Requirements References 20: Processing, Cryopreserving, and Controlling the Quality of HSC 20.1 Assessment of HSC by Measuring CD34 and the Presence of Other Cell Subsets 20.2 HSC Cryopreservation 20.3 HSC Quality Assessment 20.4 Collection of Reference Samples for Quality Control References 21: Documentation of Engraftment and Chimerism After HCT 21.1 Definition 21.2 Introduction 21.3 Methods for Chimerism Analysis 21.4 Chimerism Investigation in the Clinical Setting 21.4.1 Chimerism in Nonmalignant Diseases 21.4.1.1 Intervention to Influence the Evolution of Chimerism: Transfusion of DLI Hemoglobinopathies 21.4.2 Chimerism in Malignant Diseases References 22: Short- and Long-Term Controls After HCT 22.1 Introduction 22.2 Monitoring Depending on the Type of HCT 22.2.1 Autologous HCT 22.2.2 Allogeneic HCT 22.3 Organ-Specific Long-Term Monitoring 22.4 Fertility (See Chap. 56) 22.5 Quality of Life (See Chap. 34) References Recommended References Part IV: General Management of the Patient Topic Leaders: Selim Corbacioglu, Jan Styczynski and John Murray 23: Vascular Access 23.1 Introduction 23.2 Type of CVC Materials 23.3 Type of CVC 23.4 Venous Access 23.5 CVC Complications 23.5.1 Special Measures to Prevent Catheter-Related Infections 23.6 Catheters for Leukapheresis References 24: Transfusion Support 24.1 General Aspects 24.2 Irradiation for Prevention of Transfusion-Associated GvHD (ta-GvHD) 24.3 Prevention of CMV Transmission 24.4 Red Blood Cell Concentrates (RBCs) 24.5 Platelet Concentrates (PCs) 24.6 Immunohematological Consequences of ABO-Mismatched Transplantation 24.7 Transfusion in ABO- or RhD-Incompatible HCT 24.8 Granulocyte Concentrates References 25: Nutritional Support 25.1 Introduction 25.2 Screening for Malnutrition 25.3 Nutritional Recommendations (See General Recommendations in Table 25.1 and Fig. 25.1; Monitoring in Table 25.2 and Nutritional Strategies in Fig. 25.1) 25.3.1 Nutrition in Allo-HCT 25.3.1.1 Route of Administration 25.3.1.2 Indications and Timing 25.3.1.3 Estimation of Caloric Needs 25.3.2 Nutrition in Auto-HCT 25.3.3 Nutrition in Acute Gastrointestinal GvHD 25.3.4 Low Bacterial Diet/Low Microbial Diet/Neutropenic Diet 25.4 Immunonutrition 25.5 Long-Term Follow-Up References 26: GVHD Prophylaxis 26.1 Introduction 26.2 GVHD Prophylaxis After MAC: The “Gold” Standard Combination of CNI and MTX 26.3 GVHD Prophylaxis After RIC: Is CNI Plus MMF Standard? 26.4 New Immunosuppressive Regimens for GVHD Prophylaxis 26.5 ATG 26.6 Alemtuzumab 26.7 Naïve T-Cell Depletion 26.8 PTCy 26.9 Conclusion and Perspective References 27: Infection Control and Isolation Procedures 27.1 Introduction 27.2 Standard Precautions 27.2.1 Hand Hygiene 27.2.2 Other Standard Precautions 27.3 Transmission-Based Precautions 27.4 Management of the Threat of MDR Bacteria 27.5 HCT Environment 27.6 Food Safety in Transplant Recipients References 28: General Management of the Patient: Specific Aspects of Infectious Disease Supportive Care in Children 28.1 Management of Bacterial Infections 28.2 Management of Invasive Fungal Diseases 28.3 Management of Viral Infection and Disease 28.4 Nonpharmacological Prevention References 29: Vaccinations 29.1 General Concepts 29.2 General Principles of Vaccination in HCT Patients 29.2.1 The Pretransplant Vaccination 29.2.2 The Pre-HCT Immunity 29.2.3 The Dose of Vaccine 29.2.4 Several Patient and Vaccine Characteristics Impact on the Vaccine Response 29.2.4.1 Time from Transplantation 29.2.4.2 Type of Vaccine 29.2.4.3 Other Factors 29.2.5 Types of Vaccines in HCT Recipients 29.2.5.1 Use of IVIG and Vaccines 29.3 Benefits and Risks of Vaccination in HCT Recipients 29.3.1 Benefits 29.3.1.1 Direct Benefits 29.3.1.2 Indirect Benefits 29.3.2 Risks 29.4 Vaccination Recommendations 29.5 Specific Vaccines 29.5.1 Influenza 29.5.1.1 Clinical Manifestations 29.5.1.2 Influenza and Cardiovascular Disease (CVD) 29.5.1.3 Vaccine 29.5.2 Respiratory Syncytial Virus (RSV) 29.5.3 Measles, Mumps, and Rubella 29.5.3.1 Vaccines 29.5.4 Hepatitis B Virus (HBV) 29.5.5 Human Papilloma Virus (HPV) 29.5.5.1 Vaccine 29.5.6 Poliovirus 29.5.7 Varicella Zoster Virus (VZV) 29.5.7.1 Prevention of VZV After HCT 29.5.7.2 Types of Vaccines 29.5.8 Pneumococcus 29.5.8.1 Types of Vaccine 29.5.9 Diphtheria–Tetanus–Pertussis 29.6 Vaccinations in Children Post-allogeneic Hematopoietic Cell Transplantation 29.6.1 General Principles for Immunization Post-HCT in Children 29.6.2 Specific Recommendation for Selected Vaccines 29.6.2.1 Influenza 29.6.2.2 Pneumococcus 29.6.2.3 Meningococcus 29.6.2.4 Human Papilloma Virus 29.6.2.5 Varicella-Zoster Virus 29.6.2.6 COVID-19 29.7 Vaccinations Before Travel to Areas Endemic for Infections (See Table 29.2) (Ljungman et al. 2009) 29.8 Serological Testing 29.8.1 Prevaccination 29.8.2 Postvaccination 29.9 Vaccinations for Donors, Close Contacts/Family, and HCWs of HCT Recipients (See Table 29.3) (Ljungman et al. 2009; Cordonnier et al. 2019; Rubin et al. 2014) References 30: Psychological Morbidity and Care 30.1 Introduction 30.2 The Period Preceding HCT 30.3 Hospitalisation for HCT 30.4 Post-HCT 30.5 Family Caregivers and Related Donors 30.6 Adolescents and Young Adults (AYA) 30.7 Paediatric Patients 30.8 Psychological Interventions References 31: Clinically Relevant Drug Interactions in HCT 31.1 Introduction 31.1.1 Pharmacodynamic Interactions 31.1.2 Pharmacokinetic Interactions 31.1.2.1 Cytochrome P450 Enzyme System 31.1.2.2 Drug Transportation Monoclonal Antibodies 31.1.3 Pharmaceutical Interactions 31.2 Drug Interactions in HCT Practice 31.3 Interactions with Herbal Drugs and Food 31.3.1 Herbal Drugs 31.3.2 Food 31.4 Resources for Drug Interactions 31.5 Conclusion References 32: The Roles of the HCT Nurse 32.1 Introduction: HCT Nursing 32.2 The Roles of Nursing Throughout the Patient Transplant and Cell Therapy Pathway 32.2.1 (Central) Venous Access Devices (cVADs) 32.2.2 GvHD 32.3 The Transplant Coordinator 32.4 The Apheresis Nurse 32.5 The HCT Ward Nurse 32.5.1 Oral Mucositis (OM) 32.5.2 Sepsis 32.6 Advanced Clinical Practice Nursing in HCT 32.7 Post-HCT Nursing 32.8 Ambulatory and Day Unit Nursing 32.9 Summary References 33: Ethical Issues in HCT 33.1 Introduction 33.2 Ethical Challenges of High-Risk Treatment 33.3 Engagement with Funding Issues as a Professional Moral Obligation 33.4 The Ethical Issues in Donor Management References 34: Quality of Life Assessment After HCT for Pediatric and Adults 34.1 Introduction 34.2 QoL Assessment 34.3 Measures to Assess QoL in Adults and Pediatric Patients Undergoing HCT 34.3.1 Adults 34.3.2 Pediatrics 34.4 Challenges when Implementing QoL Assessment References Part V: HCT Complications and Management Topic Leaders: Enric Carreras, Jan Styczynski and Per Ljungman 35: Neutropenic Fever 35.1 Introduction 35.2 Initial Management of Fever During Neutropenia 35.2.1 Diagnostic Procedures 35.2.2 Evaluation of the Risk of Clinically Severe Infection 35.2.3 Evaluation of the Risk of Infection Due to Resistant Bacteria (Particularly Gram-Negative) 35.2.4 Choice of the Appropriate Empirical Antibiotic Therapy 35.2.5 In High-Risk Patient’s Assessment of the Need for Antifungal Therapy 35.3 Main Changes in the Management of Neutropenic Fever 35.3.1 De-escalation Strategy 35.3.2 Antibiotic Discontinuation 35.4 Fever Persistent despite Empirical Antibiotic Therapy References 36: Bacterial Infections 36.1 Introduction (Tomblyn et al. 2009; Averbuch et al. 2017, 2020; Misch and Andes 2019; Dandoy et al. 2020; Martinez-Nadal et al. 2020; Vu et al. 2020) 36.2 Epidemiology and Treatment of Bacterial Infections (Averbuch et al. 2017; Misch and Andes 2019; Dandoy et al. 2020; Martinez-Nadal et al. 2020; Vu et al. 2020; Trecarichi et al. 2023) 36.3 Gram-Positive Infections 36.4 Gram-Negative Infections (Paul et al. 2022; Tamma et al. 2022) 36.4.1 Broad-Spectrum β-Lactamase-Producing Enterobacterales 36.4.2 Carbapenemase-Producing Enterobacterales (CPE) 36.4.3 Pseudomonas aeruginosa (PA) 36.4.4 Other NFGNBs 36.5 Bacterial Infection Syndromes (Freifeld et al. 2011; Misch and Andes 2019; McDonald et al. 2018; Schmidt-Hieber et al. 2018; van de Beek et al. 2016) 36.5.1 Central Line-Related BSI (CRBSI) 36.5.2 Pneumonia 36.5.3 Diarrhea 36.5.4 CNS Infections 36.6 General Principles of Management of Bacterial Infections (Freifeld et al. 2011; Averbuch et al. 2013) 36.7 Prevention of Bacterial Infections (Tomblyn et al. 2009; Mikulska et al. 2018; Egan et al. 2019; Buetti et al. 2022) References 37: Invasive Fungal Diseases 37.1 Epidemiology 37.2 Diagnosis of Fungal Disease 37.3 Prevention and Prophylaxis 37.4 Treatment of Fungal Disease References 38: Viral Infections 38.1 Herpes Viruses 38.1.1 Cytomegalovirus (CMV) 38.1.1.1 Clinical Symptoms 38.1.1.2 Diagnostics 38.1.1.3 Prophylaxis 38.1.1.4 Treatment 38.1.1.5 Cellular Immunotherapy 38.1.2 HHV-6 A and B 38.1.2.1 Clinical Symptoms 38.1.2.2 Diagnostics 38.1.2.3 Prophylaxis 38.1.2.4 Treatment 38.1.3 HHV-7 38.1.3.1 Clinical Symptoms 38.1.3.2 Diagnostics 38.1.3.3 Prophylaxis 38.1.3.4 Treatment 38.1.4 HHV-8 38.1.4.1 Clinical Symptoms 38.1.4.2 Diagnostics 38.1.4.3 Prophylaxis 38.1.4.4 Treatment 38.1.5 EBV 38.1.5.1 Clinical Symptoms 38.1.5.2 Diagnostics 38.1.5.3 Prophylaxis 38.1.5.4 Treatment 38.1.6 Herpes Simplex Virus (HSV) 38.1.6.1 Clinical Symptoms 38.1.6.2 Diagnostics 38.1.6.3 Prophylaxis 38.1.6.4 Treatment 38.1.7 Varicella-Zoster Virus (VZV) 38.1.7.1 Clinical Symptoms 38.1.7.2 Diagnostics 38.1.7.3 Prophylaxis 38.1.7.4 Treatment 38.2 Community-Acquired Respiratory Viruses (CARVs) (Excluding SARS-CoV-2) 38.2.1 Epidemiology 38.2.2 Diagnostics 38.2.3 Risk Factors (RFs) 38.2.4 Management and Prevention 38.2.4.1 Pretransplant 38.2.4.2 Posttransplant 38.2.4.3 Influenza Prophylaxis Treatment 38.2.4.4 RSV Prophylaxis 38.2.4.5 Human Parainfluenzavirus (hPIV) and Metapneumovirus (HMPV) 38.3 Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Infection and Coronavirus 2019 Disease (COVID-19) 38.3.1 Clinical Symptoms 38.3.2 Diagnostics 38.3.3 General Management 38.3.4 Prophylaxis 38.3.5 Therapy 38.4 Adenovirus (ADV) 38.4.1 Clinical Symptoms 38.4.2 Diagnostics 38.4.3 Prophylaxis 38.4.4 Treatment 38.5 Polyomaviruses 38.5.1 Polyoma JCV 38.5.1.1 Clinical Symptoms 38.5.1.2 Diagnostics 38.5.1.3 Prophylaxis 38.5.1.4 Treatment 38.5.2 BKV 38.6 Norovirus 38.6.1 Clinical Symptoms 38.6.2 Diagnostics 38.6.3 Prophylaxis 38.6.4 Treatment 38.7 Flaviviruses 38.7.1 Zika Virus (ZIKV) 38.7.1.1 Clinical Symptoms 38.7.1.2 Diagnostics 38.7.1.3 Prevention 38.7.1.4 Treatment 38.7.2 Tick-Borne Encephalitis Virus (TBEV) 38.7.2.1 Clinical Symptoms 38.7.2.2 Diagnostics 38.7.2.3 Prevention 38.7.2.4 Treatment 38.8 West Nile Virus (WNV) 38.9 Human T-Cell Lymphotropic Virus (HTLV) 38.10 Viruses Covered in Other Chapters References 39: Other Life-Threatening Infections 39.1 Toxoplasmosis 39.1.1 General Concepts 39.1.2 Risk Factors and Incidence in HCT 39.1.3 Most Common Clinical Presentations 39.1.4 Diagnosis 39.1.5 Treatment and Prognosis 39.1.6 Specific Screening and/or Prophylactic Strategies Available 39.2 Tuberculosis (TBC) 39.2.1 General Concepts 39.2.1.1 Mycobacterium Tuberculosis 39.2.2 Risk Factors and Incidence in HCT 39.2.3 Most Common Clinical Presentations 39.2.4 Diagnosis 39.2.5 Treatment and Prognosis 39.2.6 Specific Screening and/or Prophylactic Strategies (Bergeron et al. 2022) 39.3 Nontuberculous (or Atypical) Mycobacterial (NTM) Infections 39.3.1 General Concepts 39.3.2 Most Common Clinical Presentations and Risk Factor 39.3.3 Diagnosis 39.3.4 Treatment and Prognosis 39.3.5 Specific Screening and/or Prophylactic Strategies Available 39.4 Listeriosis 39.4.1 General Concepts 39.4.2 Risk Factors and Incidence in HCT 39.4.3 Most Common Clinical Presentations 39.4.4 Diagnosis 39.4.5 Specific Screening and/or Prophylactic Strategies Available 39.4.6 Treatment and Prognosis 39.5 Nocardiosis 39.5.1 General Concepts 39.5.2 Risk Factors and Incidence in HCT 39.5.3 Most Common Clinical Presentations 39.5.4 Diagnosis 39.5.5 Specific Screening and/or Prophylactic Strategies Available 39.5.6 Treatment and Prognosis References 40: Bleeding and Thrombotic Complications 40.1 Introduction 40.2 Thrombotic Complications in HCT 40.2.1 Epidemiology and Risk Factors 40.2.2 VTE Prophylaxis 40.2.2.1 Randomized Studies 40.2.2.2 Multiple Myeloma 40.2.2.3 Hospitalized Patients 40.2.2.4 Prophylaxis of Catheter-Related Thrombosis 40.2.3 VTE Diagnosis and Treatment 40.2.4 Treatment of Catheter-Related Thrombosis 40.2.5 Sinusoidal Obstruction Syndrome (SOS) 40.2.6 Transplant-Associated TMA 40.3 Bleeding Complications 40.4 Thrombosis and Bleeding in CAR-T References 41: Graft Failure 41.1 Introduction 41.2 Definitions (Kharfan-Dabaja et al.2021) 41.3 Causes and Risk Factors 41.3.1 Donor Type, HLA Matching, and Graft Source 41.3.2 Graft Source and Cellular Content 41.3.3 Anti-HLA Antibodies 41.3.4 Conditioning Regimen 41.3.5 Other Factors Associated with the Development of GF 41.4 Management of GF 41.4.1 Prevention and Early Diagnosis of GF 41.4.2 Initial Measures 41.4.3 DLI, CD34 Boost, and Mesenchymal Stem Cells (MSCs) 41.4.4 Second Transplant References 42: Early Complications of Endothelial Origin 42.1 Early Complications of Endothelial Origin 42.1.1 Introduction 42.1.2 Main Characteristics of These Early Complications 42.1.3 Classification of vascular endothelial syndromes 42.1.4 Biomarkers 42.1.5 EASIX 42.2 Fluid Overload Syndrome (FOS) 42.3 Capillary Leak Syndrome (CLS) 42.4 Engraftment Syndrome (ES) 42.5 Pre-engraftment Syndrome (pES) 42.6 Thrombotic Microangiopathy Associated with HCT (TA-TMA) 42.6.1 Definition and Classification 42.6.2 Pathogenesis 42.6.3 Clinical Manifestations 42.6.4 Diagnostic Criteria 42.6.5 Clinical Forms, Incidence, Risk Factors, and Prognosis 42.6.6 Recommended Screening and Diagnostic Work-Up for TA-TMA (Fig. 42.2) 42.6.7 Treatment 42.7 Posterior Reversible Encephalopathy Syndrome (PRES) References 43: Acute Graft-Versus-Host Disease 43.1 Introduction 43.2 Definition 43.3 Risk Factors 43.4 Diagnosis and Scoring 43.5 Epidemiology 43.6 Prevention (also See Chap. 26) 43.7 Treatment 43.8 Future Perspectives: Biomarkers, Risk-Adapted Treatment, and Tissue Regeneration References 44: Chronic Graft-Versus-Host Disease 44.1 Introduction 44.2 Clinical Manifestations 44.2.1 Skin 44.2.2 Eyes 44.2.3 Oral Mucosa 44.2.4 Liver 44.2.5 Gastrointestinal Tract 44.2.6 Genitals 44.2.7 Lung 44.2.8 Joints and Fasciae 44.3 Diagnosis 44.3.1 Organ Grading of cGVHD for Adults and Children (See Annex 1 and Addendum) 44.3.1.1 Grading of Overall Severity of cGVHD (Jagasia et al. 2015) 44.4 Treatment 44.4.1 First-Line Therapy 44.4.2 Topical Therapy and Supportive Care 44.4.3 Second-Line Therapy Appendix A Appendix B Appendix C References 45: Posttransplant Lymphoproliferative Syndromes 45.1 Definitions 45.2 Types of PTLD 45.3 Pathogenesis 45.4 Clinical Manifestations 45.5 Diagnosis 45.6 Risk Factors 45.7 Grading 45.8 Treatment 45.8.1 Prevention: Donor and Recipient Issues 45.8.2 Treatment Strategies 45.8.2.1 Prophylaxis 45.8.2.2 Preemptive Therapy 45.8.2.3 Treatment of Established EBV-PTLD 45.8.2.4 Treatment in CNS Disease 45.8.2.5 Criteria of Response to Therapy in EBV-PTLD References 46: Iron Overload 46.1 Introduction 46.2 Iron Overload Before HCT (Before the Start of Conditioning) 46.3 Iron Overload During HCT (from the Start of Conditioning up to Sustained Engraftment) 46.4 Iron Overload After HCT (After Sustained Engraftment Has Been Achieved) References 47: Secondary Neoplasia (Other Than PTLPS) 47.1 Definitions 47.2 Types of Secondary Neoplasia After HCT 47.3 Pathophysiology 47.3.1 Therapy-Related Myeloid Neoplasms 47.3.2 Donor-Derived Malignancy (DDM) 47.3.3 Second Solid Neoplasms (SSN) 47.4 Frequency and Risk Factors (See Table 47.1) 47.4.1 Remarks on SSN 47.5 Screening (Majhail et al. 2012; Inamoto et al. 2015) (See Also Chap. 21) 47.5.1 Therapy-Related Myeloid Neoplasms 47.5.2 Donor-Derived Malignancy 47.5.3 Second Solid Cancer (Socie and Rizzo 2012; Inamoto et al. 2015) 47.6 Treatment 47.7 Outcome References Part VI: Specific Organ Complications Topic Leaders: Raffaella Greco and Enric Carreras 48: Ocular and Oral Complications 48.1 Ocular Complications 48.1.1 Introduction 48.1.2 Ocular GVHD 48.1.3 Posterior Segment Complications 48.1.4 Ocular Infections 48.1.5 Glaucoma 48.1.6 Cataract 48.2 Oral Complications 48.2.1 Introduction 48.2.2 Oral GVHD 48.2.3 Subsequent Oral Cancers 48.2.4 Non-GVHD-Associated Oral Complications 48.2.5 Dental Requirements of the HCT Patient References 49: Hepatic Complications 49.1 Introduction 49.1.1 Classification 49.2 Veno-Occlusive Disease in Adults 49.2.1 Introduction 49.2.2 Pathophysiology 49.2.3 Risk Factors 49.2.4 Diagnosis Criteria 49.2.4.1 Severity Grading 49.2.5 Prophylaxis and Treatment 49.3 SOS/VOD in Children 49.3.1 Introduction 49.3.2 Incidence 49.3.3 Risk Factors 49.3.4 Clinical Presentation 49.3.5 Diagnostic Criteria 49.3.6 Therapeutic Intervention 49.3.7 Prophylaxis 49.4 Hepatotropic Viruses 49.4.1 Hepatitis A Virus (HAV) 49.4.1.1 Clinical Symptoms 49.4.1.2 Diagnostics 49.4.1.3 Prevention 49.4.1.4 Treatment 49.4.2 Hepatitis B Virus (HBV) 49.4.2.1 Clinical Symptoms 49.4.2.2 Diagnostics 49.4.2.3 Prevention 49.4.2.4 Vaccination 49.4.2.5 Treatment 49.4.3 Hepatitis C Virus (HCV) 49.4.3.1 Clinical Symptoms 49.4.3.2 Diagnostics 49.4.3.3 Prevention 49.4.3.4 Treatment 49.4.4 Hepatitis E Virus (HEV) 49.4.4.1 Clinical Symptoms 49.4.4.2 Diagnostics 49.4.4.3 Prevention 49.4.4.4 Treatment 49.5 Other Hepatic Complications 49.5.1 Autoimmune Hepatitis 49.5.2 Drug-Induced Hepatitis 49.5.3 Cirrhosis 49.5.4 Hepatocellular Carcinoma (HCC) 49.5.5 Nodular Regenerative Hyperplasia (NRH) 49.5.6 Focal Nodular Hyperplasia (FNH) 49.5.7 Idiopathic Hyperammonemia 49.5.8 Cholangitis Lenta (CL) References 50: Gastrointestinal Complications 50.1 Introduction 50.2 Nausea/Vomiting 50.2.1 Definitions 50.2.2 Types 50.2.3 Pathophysiology 50.2.4 Causes 50.2.5 Diagnosis 50.2.6 Grading (CTCAE v4.0 [National Cancer Institute 2009]) 50.2.7 Treatment 50.2.8 Prophylaxis 50.2.9 Other Nausea/Vomiting 50.3 Diarrhea 50.3.1 Definitions 50.3.2 Physiopathogeny 50.3.3 Causes 50.3.4 Diagnosis 50.3.5 Grading 50.3.6 Treatment 50.4 Esophagitis/Gastritis 50.4.1 Definitions/Symptoms 50.4.2 Causes 50.4.3 Diagnosis 50.4.4 Treatment 50.5 GI Bleeding 50.5.1 Definitions/Symptoms 50.5.2 Causes 50.5.3 Diagnosis 50.5.4 Treatment 50.6 Typhlitis 50.6.1 Definitions/Symptoms 50.6.2 Causes 50.6.3 Diagnosis 50.6.4 Treatment 50.7 Pancreatic Disease 50.7.1 Definitions/Symptoms 50.7.2 Causes 50.7.3 Diagnosis 50.7.4 Treatment 50.8 Chronic Esophageal GVHD 50.8.1 Definitions/Symptoms 50.8.2 Diagnosis 50.8.3 Treatment References 51: Haemorrhagic Cystitis and Renal Dysfunction 51.1 Haemorrhagic Cystitis 51.1.1 Introduction 51.1.2 Risk Factors 51.1.3 Pathogenesis 51.1.4 Diagnosis 51.1.5 Prophylaxis 51.1.6 Treatment 51.2 Renal Dysfunction References 52: Noninfectious Pulmonary Complications 52.1 Introduction 52.2 Approach to Diagnostic Workup for Pulmonary Complications After HCT 52.2.1 Results Reported Using This Methodology (Seo et al. 2015; Lucena et al. 2014; Shannon et al. 2010; Yanik et al. 2008a, b) 52.3 Acute Noninfectious Pulmonary Complications After HCT 52.3.1 Pulmonary Edema due to Fluid Overload 52.3.2 Idiopathic Pneumonia Syndrome 52.3.2.1 Definition 52.3.2.2 Clinical Manifestations 52.3.2.3 Diagnosis 52.3.2.4 Pathogenesis, Incidence, Prese