Thomas' Hematopoietic Cell Transplantation (eBook)
John Wiley & Sons (Verlag)
978-1-118-41612-9 (ISBN)
- Extensive coverage of the field, from the scientific basis for stem-cell transplantation to the future direction of research
- Combines the knowledge and expertise of over 170 international specialists across 106 chapters
- Includes new chapters addressing basic science experiments in stem-cell biology, immunology, and tolerance
- Contains expanded content on the benefits and challenges of transplantation, and analysis of the impact of new therapies to help clinical decision-making
- Includes a fully searchable Wiley Digital Edition with downloadable figures, linked references, and more
- References for this new edition are online only, accessible via the Wiley Digital Edition code printed inside the front cover or at www.wiley.com/go/forman/hematopoietic.
Stephen J. Forman, MD Chair, Department of Hematology and Hematopoietic Cell Transplantation City of Hope Comprehensive Cancer Center Duarte, CA, USA
Robert S. Negrin, MD Professor of Medicine Chief, Division of Blood and Marrow Transplantation Stanford University Stanford, CA, USA
Joseph H. Antin, MD Professor of Medicine, Harvard Medical School Chief, Stem Cell Transplantation Dana-Farber/Brigham and Women's Cancer Center Boston, MA, USA
Frederick R. Appelbaum, MD Member and Director, Clinical Research Division Fred Hutchinson Cancer Research Center Professor and Head, Division of Medical Oncology University of Washington School of Medicine Seattle, WA, USA
Fully revised for the fifth edition, this outstanding reference on bone marrow transplantation is an essential, field-leading resource. Extensive coverage of the field, from the scientific basis for stem-cell transplantation to the future direction of research Combines the knowledge and expertise of over 170 international specialists across 106 chapters Includes new chapters addressing basic science experiments in stem-cell biology, immunology, and tolerance Contains expanded content on the benefits and challenges of transplantation, and analysis of the impact of new therapies to help clinical decision-making Includes a fully searchable Wiley Digital Edition with downloadable figures, linked references, and more References for this new edition are online only, accessible via the Wiley Digital Edition code printed inside the front cover or at www.wiley.com/go/forman/hematopoietic.
Stephen J. Forman, MD Chair, Department of Hematology and Hematopoietic Cell Transplantation City of Hope Comprehensive Cancer Center Duarte, CA, USA Robert S. Negrin, MD Professor of Medicine Chief, Division of Blood and Marrow Transplantation Stanford University Stanford, CA, USA Joseph H. Antin, MD Professor of Medicine, Harvard Medical School Chief, Stem Cell Transplantation Dana-Farber/Brigham and Women's Cancer Center Boston, MA, USA Frederick R. Appelbaum, MD Member and Director, Clinical Research Division Fred Hutchinson Cancer Research Center Professor and Head, Division of Medical Oncology University of Washington School of Medicine Seattle, WA, USA
Volume 1 6
Title Page 5
Copyright Page 6
Contents 9
Contributors 13
Preface to the First Edition 19
Preface to the Fifth Edition 20
Tribute 21
List of Abbreviations 24
Section 1 History and Use of Hematopoietic Cell Transplantation 35
Chapter 1 A History of Allogeneic and Autologous HematopoieticCell Transplantation 35
How it all began 35
History of allogeneic HCT 35
1949–1956: The humoral versus the cellular hypotheses 35
1956–1959: Early efforts in clinical marrow transplantation 35
1955–1967: Progress in animal models of allogeneic HCT 36
1968–1975: The beginning of the modern era of human marrow transplantation 36
1976–1989: Widening application of allogeneic marrow grafting for human patients 36
1989–1999: Progress in the prevention and therapy of CMV disease. New sources of grafts for allogeneic HCT 38
2000–present: Reduced intensity regimens (RIC) allow transplantation of elderly and medically infirm patients. Hematologic grafts induce tolerance for solid organ transplantation 38
History of autologous HCT 39
1958–1964: From pre-clinical studies to first clinical transplant efforts 39
1978–1995: The beginning of an era of promising results in autologous HCT 39
1986–2004: Circulating stem cells and cloned hematopoietic growth factors 39
1982–2001: Testing for minimal residual disease and efforts to “purge” grafts for autologous HCT 40
1986–1999: High-dose chemotherapy and transplantation of autologous hematopoietic cells for patients with breast cancer 40
1993–present: Research to improve preparatory regimens and efforts to consolidate post-HCT remissions 40
Conclusion 41
References 42
Chapter 2 Uses and Growth of Hematopoietic Cell Transplantation 46
Introduction 46
Changing indications for HCT 46
Changes in patient selection 47
Hematopoietic cell sources 49
Autologous transplantation 49
Allogeneic transplantation 49
Transplantation regimens and supportive care 51
Long-term survivors 52
Addressing barriers to use of HCT 52
Assessing and improving results of HCT 52
References 54
Section 2 Scientific Basis or Hematopoietic Cell Transplantation 56
Section 2a Hematopoiesis and Stem Biology Transplantation 56
Chapter 3 Generation of Definitive Engraftable Hematopoietic Stem Cells from Human Pluripotent Stem Cells 56
Introduction 56
Generation of HSCs from ESCs 57
What have we learned from murine ESCs? 57
Derivation of HSCs from hPSCs 58
Derivation of hemangioblasts from hESCs 59
Derivation of blood-specific lineages from hPSCs 59
T cells 59
B cells 59
NK cells 59
Macrophages 60
Dendritic cells 60
Erythroid cells 60
Megakaryocytes/platelets 60
Isolation and/or expansion of hPSC-derived HSCs 61
Are PSC-derived hematopoietic progenitors capable of engraftment and hematopoietic repopulation? 61
Transplantation of HSCs derived from mPSCs 61
Transplantation of HSCs derived from human PSCs 62
Can we generate immunologically compatible HSCs? 62
Creation of a global hPSC bank 62
Immune privileged? 62
Pluripotent stem cells tailor-made by reprogramming patients’ somatic cells (iPS) 63
Direct reprogramming of patients’ fibroblasts into blood cells 63
Conclusion 63
References 65
Chapter 4 Hematopoietic Stem Cells, Regenerative Medicine, and Leukemogenesis 67
Introduction 67
Failure of hematopoietic cell transplanters and journals to use appropriate terms to describe the cells that are transplanted 67
History of the HSC 67
Properties of mouse HSCs and other MPPs 68
Genetic pathways for the self-renewal of HSCs 69
Migration of HSCs 71
Hematopoietic stem cell and progenitor niches 72
Ontogeny of HSCs 72
The aging of HSCs: clonal selection versus regulated epigenetic change 75
Does hematopoiesis only derive from HSCs and do HSCs give rise only to blood? 75
The transition from discovery to accepted scientific fact 76
Lineage committed hematopoietic progenitor cells 76
Considerations for the definition/isolation of hematopoietic progenitors 76
Common lymphoid progenitor cells and lymphoid development 76
Common myeloid progenitor cells and myeloid development 78
Alternative developmental pathways 79
Human myeloid progenitors 79
Lineage commitment in fetal hematopoiesis 79
DC development 80
Gene expression profiles of HSCs and their oligolineage progenitors: Gene Expression Commons 80
Promiscuous expression of multiple myeloid or lymphoid genes in hematopoietic branchpoints 81
Downregulation of genes irrelevant to committed lineages as a critical mechanism of lineage restriction 82
Transplantation of HSCs in mouse and human 83
Graft engineering 84
Immunologic tolerance and HSC transplantation 86
Reversing autoimmune diseases with disease-resistant HSCs 86
The future of HSC transplantation: replacing myeloablative conditioning with selective depletion of endogenous HSCs and living donors with cell lines as donors 86
Stem cell competition and natural chimeras 86
Myelogenous leukemias are driven by leukemia stem cells (LSCs), which are at the oligolineage progenitor stages 87
Progression to myelogenous leukemias occurs in competitive HSC clones in a stepwise fashion involving both mutations and epigenetic events 87
Final leukemic transformation can occur at the level of myeloid progenitors 89
Programmed cell death and programmed cell removal are initiated by proto-oncogenic events, and all leukemias (and cancers) overcome both to become LSCs (CSCs) 90
Myelodysplastic syndrome is a stage of leukemic progression before programmed cell removal is overcome 90
CD47, the “don’t eat me” signal that overcomes programmed cell removal, is a target for antileukemia and anticancer therapies 91
Conclusions 91
References 92
Chapter 5 Marrow Microenvironment and Biology of Mobilization of Stem Cells 100
Introduction 100
Stem cell homeostasis and the components of the bone marrow niche 100
Regional differences within the bone marrow 101
HSC homing and engraftment 104
HSPC mobilization via ablation of niche cell subsets 105
Stem cell mobilization 105
Clinically available mobilizing agents 105
Mobilization of HSPCs with G-CSF 105
CXCR4/CXCL12 axis and G-CSF mobilization 105
Cellular mediators of G-CSF mobilization 107
G-CSF mobilizes HSPCs through a hematopoietic intermediate 107
G-CSF suppresses osteoblast lineage cells in the bone marrow 107
G-CSF mobilizes HSPCs through the sympathetic nervous system 107
HSPC mobilization via pharmacologic disruption of the CXCR4/CXCL12 axis 108
Mobilization of HSPCs with the CXCR4 antagonist plerixafor 108
Plerixafor and G-CSF mobilize phenotypically different CD34+ cell subsets 109
Alternative agents to disrupt the CXCR4/CXCL12 axis 109
Mobilization of HSPCs using CXCR4 agonists 109
HSPC mobilizing agents that target VLA-4 110
Mobilization of murine HSPCs by small molecule antagonists of VLA-4 110
Other biologic factors involved in mobilization 110
Parathyroid hormone (PTH) and mobilization 110
Complement and mobilization 110
Hypoxia, HIF-1? and mobilization 111
Bioactive sphingolipids and mobilization 111
Conclusion 111
References 112
Chapter 6 Expansion of Human Hematopoietic Stem Cells 118
Introduction 118
Initial attempts at ex vivo stem cell expansion for clinical application using cytokine-based expansion systems 118
Pre-clinical approaches for ex vivo HSPC expansion: intrinsic and extrinsic regulators of cell fate 120
Notch signaling in hematopoiesis 121
Clinical trials using ex vivo expanded/manipulated cord blood HSPC 121
Rationale 121
Notch-mediated ex vivo expansion systems for clinical application 122
Other emerging approaches to ex vivo expansion 123
Alternative strategies to overcome the limiting cell dose in CB grafts: ex vivo modulation to enhance HSC homing 123
Conclusion 124
References 125
Chapter 7 Mesenchymal Stromal Cells and Hematopoietic Cell Transplantation 127
Introduction 127
Brief history of MSCs 127
Nomenclature 127
Biologic role of MSCs in situ 128
Working definition of ex vivo-expanded MSCs for clinical cell therapy 129
Cell biology of ex vivo expanded MSCs 129
Tissue sources 129
Isolation 129
Phenotype 129
Ex vivo expansion 130
Secretome 130
Homing and migration 130
Lifespan of MSCs 130
Immunobiology 130
T lymphocytes 130
B lymphocytes 131
NK cells 131
Dendritic cells (DCs) 131
General mechanisms of immune modulation 131
Immune privilege 131
Risks of ex vivo expanded MSCs as cell therapy 132
Malignant transformation 132
Ectopic tissue formation after systemic infusion 133
Opportunistic infections 133
Clinical applications 133
MSCs to foster engraftment of HSCs following HCT 133
Hematopoietic stem cell expansion 134
MSCs to treat GVHD 134
Future considerations 135
References 136
Chapter 8 Genetic Manipulation of Hematopoietic Stem Cells 138
Introduction and history 138
Gene transfer vectors 138
Retroviral vectors 138
Gammaretroviral vectors 139
Lentiviral vectors 139
Foamy viral vectors 140
Retroviral pseudotypes for HSC gene transfer 140
Other vector systems 141
Gene editing and targeted gene integration 141
Gene transfer to HSCs 142
Source of HSCs for gene transfer 142
Ex vivo culture conditions 142
In vitro assays for HSC gene transfer 143
Gene transfer to mouse HSCs 143
Immunodeficient xenotransplant mouse models 143
Gene transfer to large-animal repopulating cells 144
In vivo delivery of transgenes to HSCs 144
Expansion of gene-modified cells prior to infusion 144
Expansion of gene-marked cells in vivo 145
Immune responses to transgenes 146
Clinical trials of HSC gene transfer 146
Early studies 146
Genetic diseases 146
Severe combined immunodeficiency syndrome (SCID) 146
SCID-X1 148
ADA deficiency 148
X-linked chronic granulomatous disease 149
Wiskott-Aldrich syndrome 150
?-Thalassemia 150
Fanconi anemia 151
Lysosomal storage disorders 151
X-linked adrenoleukodystrophy 151
Metachromatic leukodystrophy 152
Solid tumors 152
Glioblastoma multiforme 152
Infectious disease 153
HIV 153
Vector-mediated insertional mutagenesis 154
Leukemia in the SCID-X1, chronic granulomatous disease and Wiskott-Aldrich syndrome trials 154
Deregulation of host genes by vector proviruses 154
Approaches to reduce the potential for vector-mediated malignancy 155
Summary and future directions 155
References 156
Section 2B Immunology 160
Chapter 9 Overview of Hematopoietic Cell Transplantation Immunology 160
Introduction 160
Fundamental differences between pathogen and transplantation responses 160
Fundamental differences between hematopoietic cell transplantation and solid organ transplantation 160
Transplantation antigens 161
Major histocompatibility antigens 161
HLA matching 161
Structure of HLA and cell biology of antigen presentation 161
Minor histocompatibility antigens 163
Differences in responses against major and minor antigens 163
Movement of cells in the immune system 163
Innate and adaptive immune responses 163
Regulation of natural killer-cell responses 164
Self-tolerance and antigen recognition by T cells 165
Molecules used for recognition of antigens 165
TCR signaling 165
Selection of T cells in the thymus 165
T-cell activation, effector differentiation, and effector functions 165
Activation of T cells by antigen-presenting cells 165
T-cell differentiation 166
Costimulatory molecule and cytokine receptor signaling 167
Proinflammatory T-cell effector functions 167
Peripheral tolerance and regulation of T-cell responses 168
T-cell memory 168
Selection of donors for allogeneic HCT 169
Outcomes influenced by genetic disparity between the donor and recipient 169
Engraftment 169
Acute GVHD 170
Chronic GVHD 172
Graft-versus-leukemia effects 172
Development of tolerance 173
Immune reconstitution 173
Pathways of T-cell reconstitution 173
Effects of GVHD on immune reconstitution 174
Opportunistic infections as an indicator of impaired immune reconstitution 174
Approaches for enhancement of immune reconstitution 174
Summary and conclusions 175
References 176
Chapter 10 Histocompatibility 179
Introduction 179
HLA genes: structure and function 179
The class I region 181
The class II region 182
The class III region 183
The history of HLA 183
The early period: 1964–1972 184
The middle period: 1975–1984 184
The later period: 1987 to the present day 184
Nomenclature 187
Hallmarks of the MHC: linkage disequilibrium (LD) and haplotypes 187
Intergenic variation within the MHC 188
KIR genes and haplotypes 189
Models for donor inhibitory KIR-mediated killing 189
Histocompatibility testing of donors for allogeneic transplantation 189
Typing methods 189
Donor selection 191
Conclusions 192
References 193
Chapter 11 Natural Killer Cells and Allogeneic Hematopoietic Cell Transplantation 195
Introduction 195
NK-cell subpopulations: CD56bright and CD56dim NK cells 195
NK cell Cytotoxicity 196
MHC-specific NK-cell receptors: KIR and CD94/NKG2A 196
The “missing self” hypothesis 196
KIR receptors 196
NKG2A 197
NK-cell-activating receptors: NKG2D, natural cytotoxicity receptors, and DNAM-1 198
NKG2D 198
Natural cytotoxicity receptors (NCRs) 198
DNAM-1 198
NK killing of leukemia 198
NK-cell development from hematopoietic progenitor cells 199
Innate lymphoid cells (ILCs) 200
Development of NK-cell self-tolerance 201
NK-cell reconstitution after allo-HCT 201
NK-DC interactions 201
NK cells, viral infections, and “NK memory” 202
Clinical studies 202
Adoptive NK-cell transfer for refractory leukemia and cancer 203
Conclusion 204
References 205
Chapter 12 Mechanisms of Tolerance 208
Introduction 208
General mechanisms of alloreactive T-cell immune tolerance 208
Clonal deletion 208
Ignorance 209
Anergy 209
Exhaustion 209
Suppression 210
Induction of host immune tolerance to organ allografts 213
Major non-chimeric transplantation tolerance-inducing regimens 213
Clinical regimens for induction of chimerism and transplantation tolerance 214
Summary and future directions 217
Acknowledgments 217
References 218
Chapter 13 The Pathophysiology of Graft-versus-Host Disease 222
Acute GVHD pathophysiology: a three-step model 222
Step 1: effects of conditioning 222
Step 2: Donor T-cell activation and cytokine secretion 222
Donor T-cell activation 222
Cytokine secretion by donor T cells 223
Step 3: cellular and inflammatory effectors 224
Cellular effectors 224
Inflammatory effectors 224
Toll-like receptors (TLRs) and innate immunity 224
GVHD prevention: from animal models to clinical practice 225
Step 1: reduced-intensity conditioning regimens 225
Step 2: modulation of donor T cells 225
Reduced T-cell numbers 225
Reduced T-cell activation 226
Reduced T-cell proliferation 226
Step 3: blockade of inflammatory stimulation and effectors 227
Reduced exposure to organisms 227
Blockade of effectors 227
Chronic GVHD 227
Conclusion 228
References 229
Chapter 14 Immune Regulation in Hematopoietic Cell Transplantation 232
Introduction 232
Regulatory cell populations 232
The role of natural regulatory T cells in GVHD suppression 233
Ex vivo expansion of Treg cells 233
Critical requirements for Treg-cell function 234
Treg-cell homeostasis in vivo 234
Clinical translation of Treg-cell biology 234
Role of Treg cells in human GVHD 235
Adoptive transfer of Treg cells in allogeneic HCT 235
Impact of immunosuppressive medications on Treg?cell function 236
Activation and expansion of Treg cells in vivo 236
Natural killer T cells 237
Mesenchymal stromal cells 237
Myeloid-derived suppressor cells 238
Other regulatory populations 238
Conclusion 238
References 239
Chapter 15 Immune Reconstitution Following Hematopoietic Cell Transplantation 242
Introduction 242
Steady-state lymphopoiesis 242
What are the causes of post-transplant immune deficiencies? 243
Relationship between recipient conditioning and immune reconstitution 243
Relationship between graft composition and immune reconstitution 243
Impact of GVHD on immune regeneration after HCT 244
Consequences of prolonged immune depletion 244
Endogenous immune reconstitution after HCT 244
Reconstitution of innate immunity 244
Reconstitution of adaptive immunity 244
Functional analysis of T-cell reconstitution (monitoring) 244
Therapeutic strategies to improve immune reconstitution 246
Cytokines and growth factors 246
Hormone therapies 247
Cellular therapies 247
Combination therapies 247
Conclusion 247
References 248
Chapter 16 Biology of the Human Graft-versus-Tumor Response and How to Exploit It 252
Defining characteristics of the graft-versus-tumor effect in human allogeneic hematopoietic cell transplantation 252
Identifying the genetic determinants, effector cells, and target molecules of the GVT effect 252
Autologous and syngeneic HCT 252
Allogeneic HCT 253
Strategies for exploiting the GVT response 259
Identifying genomic loci associated with GVT activity 259
Donor selection 260
Donor or recipient vaccination 260
Adoptive cellular therapy – donor lymphocytes 261
Adoptive cell therapy with manipulated donor lymphocytes 262
Adoptive therapy with regulatory T cells 263
Strategies for improving the safety and efficacy of adoptive cell therapy 263
Conclusion 263
References 264
Chapter 17 Dendritic Cells in Hematopoietic Cell Transplantation 268
Introduction: the dendritic cell network 268
Classical or conventional DCs (DCs) (Figure 17.1) 268
DCs in non-lymphoid tissues (Figures 17.2 and 17.3) 268
Epidermal Langerhans cells (LCs) 269
Tissue migratory DCs 269
Plasmacytoid DCs (PDCs) 271
Human DCs 271
In vitro-derived DCs and PDCs 271
DC functions 271
Antigen presentation 272
Stimulation of allogeneic T cells 272
Functions of PDCs 273
Non-professional APCs 273
DC homeostasis in the steady state 273
Monocyte-derived DCs at sites of inflammation 273
Response of DCs to conditioning therapy 274
Conditioning 274
Effect of conditioning on blood DCs 274
Effect of conditioning on tissue DCs (Figure 17.4) 274
Mechanisms of conditioning-induced DC depletion 274
Qualitative effects of conditioning on DCs 275
Homeostasis after transplant: content of the graft 275
Numerical recovery of DCs 275
Blood DC chimerism 275
Peripheral tissue DC chimerism (Figure 17.5) 275
Acute GVHD 277
Early work 277
More recent studies 277
Persistence of recipient LCs 277
APCs that induce GVHD 277
GVHD kinetics 278
GVHD tropism 278
Chronic GVHD 278
GVL effect 279
DCs as potential therapeutic targets in transplant settings 280
Conclusion 280
References 281
Chapter 18 The Experimental Basis for Hematopoietic Cell Transplantation for Autoimmune Diseases 285
Introduction 285
The immune response 285
Induction and perpetuation of immune responses 285
Control of immune reactivity 286
Autoimmune pathology 287
Genes and environment 288
What triggers autoreactivity? 290
Animal models of ADs 290
Spontaneously arising ADs 291
Immunization and cell transfer models of ADs 292
Genetic engineering of ADs 292
HCT and the treatment of ADs 293
Historical perspective 293
ADs as “stem-cell disorders” 294
Rationale for HCT to treat ADs 294
Definition of terms and experimental approaches 295
Autologous HCT 296
Proof of concept 296
Autologous HCT in different disease phases 297
Failures of autologous HCT: does T-cell depletion improve the outcome? 297
Autologous transplantation augmented by gene therapy 298
Allogeneic HCT 298
Treatment of spontaneous ADs with allogeneic HCT 299
Competitive advantage of autoimmune HSC? 299
Transplantation of purified HSCs 300
Allogeneic HCT and antigen-induced ADs 300
Mechanisms by which allogeneic HCT abrogates autoreactivity 303
Conclusion 304
References 305
Section 2C Technical Aspects 309
Chapter 19 Pharmacologic Basis for High-dose Chemotherapy 309
Introduction 309
Pharmacology of drugs used in high-dose chemotherapy 309
Alkylating agents 309
Topoisomerase inhibitors 315
Nucleoside analogs 316
Conclusion 319
References 321
Chapter 20 High-dose Preparatory Regimens 323
Introduction 323
Evaluation of new treatment regimens 323
Marrow ablative agents – maximum tolerated dose (MTD) when administered with HCT (Table 20.1) 323
Total body irradiation (Tables 20.1–20.4) 323
High-dose chemotherapy regimens (Tables 20.5–20.9) 324
Alkylating agents 325
Melphalan (Tables 20.1 and 20.7) 327
ThioTEPA (Tables 20.1 and 20.8) 327
Non-marrow ablative agents and agents for which MTD with stem-cell support is not known 328
Cyclophosphamide (Table 20.1) 328
Ifosfamide (Table 20.1) 328
Etoposide (Tables 20.1 and 20.9) 328
Fludarabine 328
Mitoxantrone (Tables 20.1 and 20.7) and doxorubicin (Table 20.9) 328
Cisplatin (Table 20.1) 328
Carboplatin (Table 20.1) 328
Cytarabine (Table 20.1) 329
Paclitaxel 329
High-dose regimens with total body irradiation 329
Total body irradiation with cyclophosphamide (Table 20.2) 329
Randomized trials involving different TBI regimens (Table 20.3) 329
Total body irradiation with drugs other than cyclophosphamide (Table 20.4) 329
Cyclophosphamide and total body irradiation with other drugs (Table 20.4) 329
High-dose chemotherapy versus high-dose chemoradiotherapy (Table 20.10) 329
Modified total body irradiation regimens 330
Marrow ablation using targeted radioisotopes 330
Bone-seeking radioisotopes 330
Sequential regimens with peripheral blood hematopoietic cell support 330
Allogeneic transplantation with non-marrow-ablative regimens 331
Conclusion 331
References 332
Chapter 21 Reduced-intensity Allogeneic Transplantation Regimens 335
Introduction 335
Preclinical canine studies 335
Clinical results 336
HLA-matched related HCT 337
HLA-mismatched related HCT 339
HLA-matched and mismatched unrelated HCT 340
Chimerism and engraftment kinetics 341
GVHD and GVT effects 341
Toxicities 342
Comparing morbidity and mortality: influence of pre-transplant comorbidities 344
Consolidative reduced-intensity allografts following planned autografts 344
Reduced-intensity allografting after failed high-dose transplants 345
Conclusion 345
References 347
Chapter 22 Radiotherapeutic Principles of Hematopoietic Cell Transplantation 350
Introduction 350
Radiobiology principles 350
Radiation physics and physical considerations 351
High-dose TBI-containing regimens: clinical results 352
High-dose TBI schedules utilized 352
Dose rate 354
Organ shielding 354
High-dose TBI-containing regimens: normal tissue effects 355
Acute toxicities associated with high dose TBI-containing regimens 355
Lung: interstitial pneumonitis 355
Renal toxicity 356
Sinusoidal obstructive syndrome 356
Cataract formation 356
Second malignancy induction 357
High-dose TBI versus non-TBI regimens 357
TBI and reduced-intensity conditioning (RIC) regimens 358
Total lymphoid irradiation (TLI) 360
Involved field radiotherapy 361
Targeted total body irradiation and future directions 361
Key points 363
References 364
Chapter 23 Radioimmunotherapy and Hematopoietic Cell Transplantation 368
Background 368
Components of RIT 369
Target antigen selection 369
Antibody selection 370
Antibody pharmacology 371
Labeling procedures 371
Dosimetry 372
Radiation effects 372
Leukemia 373
Non-Hodgkin lymphoma 375
Hodgkin lymphoma 378
Solid tumors 378
Toxicity 378
Future directions 379
Conclusion 381
References 382
Chapter 24 Documentation of Engraftment and Characterization of Chimerism After Hematopoietic Cell Transplantation 386
Genetic markers in hematopoietic cell transplantation 386
Methods for evaluating chimerism 386
Historical perspective 386
Molecular cytogenetics 387
VNTR and STR polymorphisms 387
DNA amplification of other loci for assessment of chimerism 391
Clinical application of chimerism tests 391
Samples used for chimerism testing 391
General principles 391
Chimerism testing in patients at risk for graft failure 392
Chimerism testing in patients at risk for recurrent malignancy 392
Chimerism testing after reduced-intensity conditioning regimens 393
Other applications for genetic marker studies 393
Biologic insights from genetic marker studies 394
Conclusion 394
References 395
Chapter 25 The Detection and Significance of Minimal Residual Disease 397
Introduction 397
Methods of MRD detection 397
Chromosomal assays 397
Flow cytometry assays 397
Polymerase chain reaction (PCR) 397
High-throughput sequencing 398
The clinical significance of MRD 401
MRD detection in acute lymphoblastic leukemia (ALL) patients receiving chemotherapy 401
MRD in ALL in the transplant setting 403
MRD detection in acute myeloid leukemia (AML) following chemotherapy 404
MRD in AML in the HCT setting 405
MRD in chronic myelogenous leukemia (CML) following tyrosine kinase inhibitor (TKI) therapy 405
MRD detection in CML after transplantation 405
MRD in chronic lymphocytic leukemia (CLL) 406
MRD testing in multiple myelomaMM 406
Not all patients with detectable MRD progress to relapse 407
Conclusion – the future of MRD 407
References 408
Chapter 26 Pathology of Hematopoietic Cell Transplantation 413
Introduction 413
Pre-transplant evaluation 413
Hematopoietic system 413
Toxicity from cytoreductive therapy 414
Pre-transplant hepatic disease 414
Hepatic sinusoidal obstructive syndrome (veno-occlusive disease) 416
Post-transplant hematopoietic evaluations 419
Role of the microvasculature in transplant complications 421
Graft-versus-host disease 422
Immunopathogenesis 422
Immunohistology 423
Surgical pathology of GVHD 424
Acute versus chronic GVHD 425
Grading of GVHD 425
Skin 426
Utility of skin biopsies in GVHD 426
Grading of GVHD in the skin 426
Differential diagnosis of Grade I/II GVHD 426
Differential diagnosis of Grade III/IV GVHD 428
Chronic GVHD of the skin 429
Oral GVHD 432
Gastrointestinal GVHD 432
Spectrum of gastrointestinal GVHD 434
Differential diagnosis 436
Esophageal GVHD 437
Autologous GVHD 437
Hepatic GVHD 438
Differential diagnosis 441
Pulmonary complications 442
Interstitial pneumonia syndrome 443
Pulmonary GVHD 443
Other sites involved in chronic GVHD 444
Infection 445
Additional comments 449
References 450
Chapter 27 Biostatistical Methods in Hematopoietic Cell Transplantation 454
Introduction 454
Statistical methods in HCT research 454
Survival analysis 454
Kaplan–Meier survival estimate 454
Competing risks 455
Testing of group differences for time-to-event end-points 456
Regression 457
Healthy approach to modeling 457
Variable selection and modeling specifications 458
Logistic regression 458
Cox regression 458
Competing-risks regression 459
Multiple comparisons 459
Clinical trial design in HCT research 460
Phase 0 clinical trials 460
Phase I clinical trials 460
Phase II clinical trials 461
Phase III clinical trials 462
Observational study designs 464
Retrospective cohort study 464
Retrospective case–control studies 465
Prospective cohort study 465
References 466
Chapter 28 Outcomes Research in Hematopoietic Cell Transplantation 467
Introduction 467
Definition 467
History 467
Specific questions for the field of HCT 469
What are the costs of HCT, and how can they be reduced? 469
Are the clinical benefits of HCT worth the monetary costs? 469
What is the patient’s experience with HCT? 470
How are patient-reported measures developed? 472
How can one combine information from several different data sources? 472
How can the practice of HCT be improved through health services research? 473
Conclusion 474
References 475
Section 3 Patient-oriented Issues in Hematopoietic Cell Transplantation 477
Chapter 29 The Evaluation and Counseling of Candidates for Hematopoietic Cell Transplantation 477
Introduction 477
Written information for patients 477
The patient’s first visit to the transplant center 477
Advice on counseling new patients 477
The problem of permanent infertility 478
The choice of transplant procedure 479
Which outcomes data should one quote? 479
What does the patient hear and remember? 479
The second counseling meeting 479
When to advise against HCT 480
How to counsel patients seeking multiple opinions 480
The new foreign patient 480
The issue of clinical trials 481
Conditions affecting treatment outcomes 481
Disease and remission status 481
Compatibility of the donor–recipient pair 481
Performance status 482
Prior and maintenance therapies for the underlying diseases 482
Comorbid conditions 483
Nutritional status 484
Comorbidity assessment 484
Age of the transplant candidate 484
Ethnicity, race, and socioeconomic issues 485
Previous infections 485
Transfusion history 485
Psychosocial assessment 486
Special considerations for pediatric transplant candidates 486
The matter of consent 486
Initial visit by the patient and parents 486
Children with malignant disease 486
Children with non-malignant disease 487
Conditions affecting the child as a candidate for HCT 487
Counseling the patient and family 488
Advanced care planning (ACP) 489
Some final considerations 489
References 490
Chapter 30 Nursing Role in Hematopoietic Cell Transplantation 494
Introduction 494
Prework-up/prior to arrival at the transplant center (Table 30.1) 495
Work-up (Table 30.2) 495
Preconditioning (Table 30.3) 496
Donor preparation (Table 30.4) 496
Mobilization and collection (autologous patients and allogeneic donors) (Table 30.5) 496
Conditioning (Table 30.6) 496
Bone marrow harvest (Table 30.8) 498
Transplant phase (Table 30.9) 498
Pre-engraftment (Table 30.10) 498
Early post-engraftment (Table 30.11) 501
Intensive care management of the transplant patient 502
Relapse post-transplant 502
Discharge (Table 30.12) 502
Long-term recovery (Table 30.14) 502
Nursing practice issues in hematopoietic stem-cell transplant 504
Conclusion 505
Acknowledgments 505
References 506
Chapter 31 Ethical Issues in Hematopoietic Cell Transplantation 507
Introduction 507
Who is eligible for HCT? 507
Case scenario 1 507
Case scenario 2 507
Informed consent for patients undergoing HCT 508
Case scenario 3 508
Case scenario 4 508
Informed consent for donors of hematopoietic cells 509
Case scenario 5 509
Case scenario 6 509
Alternative sources of hematopoietic cells 512
Case scenario 7 512
Transplantation for non-malignant diseases 513
End-of-life issues 514
Case scenario 8 514
Conclusion 516
References 517
Chapter 32 Psychosocial Issues in Hematopoietic Cell Transplantation 519
Introduction 519
Factors influencing psychosocial issues in HCT 519
Prominent psychosocial stressors in HCT 520
Stages of HCT and associated psychosocial issues 520
Stage I: the decision to undergo HCT 520
Stage II: preparative regimen and recovery of marrow function 522
Stage III: hospital discharge and early recovery 523
Stage IV: long-term recovery 523
Psychosocial Issues in HCT: informal caregivers 525
Conclusion 526
References 527
Chapter 33 Assessment of Quality of Life in Hematopoietic Cell Transplantation Recipients 529
Introduction 529
Definition of health-related QOL 529
Dimensions of QOL 530
Phases of HCT and related risk factors for QOL outcomes 531
Pre-transplant 531
Acute treatment 531
Recovery 531
Long-term function and late effects 532
Pediatric QOL 532
Caregivers and parents of transplant recipients 532
QOL measurement 532
Clinical utility of QOL data 533
Generic measures 534
HCT-specific measures 534
QOL measurement methods 534
Pediatric QOL assessment 535
Conclusion 535
Acknowledgment 535
References 536
Chapter 34 Sexuality Following Hematopoietic Cell Transplantation 539
Introduction 539
Conceptualizing sexuality 539
Alterations in sexual health following HCT 539
Etiology of altered sexual health in HCT recipients 541
Biologic and physiologic variables in men 541
Biologic and physiologic variables in women 542
Psychologic and social variables 542
Assessment and interventions for altered sexual health 543
Hypoactive sexual desire disorder 544
Premature ovarian failure, vaginal atrophy, and dyspareunia 544
Erectile dysfunction 545
Areas for future research 546
Conclusion 546
References 547
Chapter 35 Hematopoietic Cell Transplantation: The Patient’s Perspective 549
Preparing for transplant 549
Put the risks into perspective 549
Communication in lay language 550
Repetition and reinforcement are important 550
Different learning styles 550
Discussing pain control is important 551
Discuss psychologic difficulties 551
Psychosocial support networks for patients and their families 552
Quality of life post-transplant 552
Chronic GVHD 554
Other resources for patients and survivors 554
BMT InfoNet 554
Be the Match/National Marrow Donor Program 554
National BMT-Link (www.nbmtlink.org) 555
Center for International Blood and Marrow Transplant Research 555
The Children’s Oncology Group 555
National Institutes of Health 555
Other resources 555
Conclusion 555
References 556
Section 4 Sources of Hematopoietic Cell for Hematopoietic Cell Transplantation 557
Chapter 36 Hematopoietic Cell Procurement, Processing, and Transplantation: Standards, Accreditation, and Regulation 557
Introduction 557
Governmental regulation 557
Role of the FDA 557
Cord blood cells 558
State regulation 559
Stem cell Acts 559
Voluntary professional accreditation 559
Foundation for the Accreditation of Cellular Therapy (FACT) 559
AABB 564
Standards 564
National Marrow Donor Program 565
Other Standards 565
Future directions 565
References 566
Chapter 37 Bone Marrow and Peripheral Blood Cell Donors and Donor Registries 568
Introduction 568
Products from HC donors 568
Donors of allogeneic bone marrow and PBPC 568
Unrelated donors and unrelated donor registries 568
Donor eligibility and qualification 569
Regulatory requirements 569
Medical suitability 570
Ethical and psychosocial issues 571
Donation procedures 571
Bone marrow 571
Peripheral blood HCs 572
Adverse events associated with hematopoietic cell donation 572
Additional adverse events specifically associated with marrow donation 572
Serious adverse events following marrow donation 573
Additional adverse events associated specifically with PBPC donation 573
Serious adverse events following peripheral blood hematopoietic cell donation 573
PBPC versus marrow: which is easier for donors? 574
Special considerations 574
Infants and children as HC donors 574
Subsequent donations following an initial HC donation 574
Growth factor-mobilized bone marrow 575
Summary 575
References 576
Chapter 38 The Role of the Transplant Program in a Nuclear Accident or Terrorism 578
Introduction 578
Preparedness and planning for a nuclear detonation 578
Responding to the consequences of a nuclear incident: concepts, information and resources 580
Medical management of acute responses to radiation 580
The essential role of biodosimetry 580
Radiation Injury Treatment Network (RITN) 581
Resources for assisting hematologists with clinical management 582
A role for stem cell transplantation? 582
Current efforts to develop medical radiation countermeasures 583
Conclusion 583
References 584
Chapter 39 Cord Blood Hematopoietic Cell Transplantation 585
Introduction 585
Brief historical perspective of the first CB HCTs 585
CB banking 586
Clinical results 587
Related or familiar CB for allogeneic HCT in children 587
Related CB for malignant disorders 587
Directed donor CB banking 588
Clinical use of unrelated CB cells for allogeneic HCT 588
Unrelated CB HCT in children 588
Malignant hematologic diseases 588
Non-malignant hematologic diseases 590
Unrelated CB HCT in adults 590
Results of unrelated CB 592
Selection of CB units 594
Other considerations when selecting a cord blood unit 595
Improving outcomes after CB HCT 596
Immune reconstitution after CB HCT 596
Clinical immune outcomes following UCB transplantation 597
Future directions for enhancing CB HCT 597
Potential means to increase numbers of collected CB cells and/or ex vivo expand CB HSC and HPC 597
Efforts to enhance the homing and subsequent nurturing effect of the microenvironment on CB HSC 598
Possibilities for regenerative medicine with cells present in or generated from CB 598
References 600
Chapter 40 Mobilization of Peripheral Blood Hematopoietic Cells for Autologous HCT 604
Introduction 604
Identification and enumeration 604
Mechanisms of hematopoietic cell mobilization 604
Evidence for the pivotal role of SDF-1/CXCR4 in HSC mobilization and trafficking 605
Role of proteases and other cell adhesion molecules on HSC mobilization 606
Clinical applications 606
Collection techniques 606
Identifying the optimal cell yield 606
Cytokine and cytokine plus chemokine-induced mobilization 607
Combination cytokine, pegylated cytokine, and cytokine plus chemotherapy-induced mobilization 608
Factors affecting yield of PBPC mobilization 609
Managing poorly mobilizing patients 609
Tumor contamination 610
Future directions 610
Summary 611
References 612
Chapter 41 Peripheral Blood Hematopoietic Cells for Allogeneic Transplantation 615
Introduction 615
The donors 615
Mobilization and collection of HCs from PB 615
Characteristics and dose of HCs from PB or marrow 616
T lymphocytes and other immune cells in mobilized blood 617
Side-effects and long-term sequelae of mobilization and collection of HCs 618
The recipients 619
Randomized trials in leukemia patients with HLA-identical family donors 619
Marrow or mobilized blood: the meta-analysis 621
Mobilized BM for allogeneic transplantation 622
Allogeneic PBHCT in diseases other than leukemia 622
Allogeneic PBHCT in children and adolescents 622
T-cell-depleted mobilized blood 623
Unrelated donor transplants 623
Conclusion and future developments 623
References 624
Chapter 42 Cryopreservation of Hematopoietic Cells 627
Introduction 627
Non-frozen storage of HC products 627
Cryopreservation theory 628
The chemistry and biology of mammalian cell cryopreservation 628
Induction of apoptosis during cell cooling 630
The physics of cooling and warming of cell products 630
Cryoprotectant solutions 630
DMSO 630
HES 631
Protein 631
Salt and sugar content 632
Cryopreservation technique 632
Evaluation of cryopreservation efficacy 632
Processing of HC products for cryopreservation 632
Cell concentration 633
Rates of cooling and warming 633
Storage of cryopreserved cells 633
Post-thaw manipulation 634
Cryoprotectant toxicity 635
Toxicity to HCs 635
Toxicity to the HCT recipient 635
Special considerations 636
Cryopreservation of HCs intended for allogeneic transplantation 636
Tumor cell purging 636
Summary 637
References 638
Chapter 43 Use of Recombinant Growth Factors after Hematopoietic Cell Transplantation 640
Introduction 640
Erythropoietin 640
Recombinant human EPO after autologous HCT 640
rHuEPO after allogeneic HCT 640
Summary: clinical use of EPO after HCT 641
Granulocyte colony-stimulating factor 642
G-CSF after autologous HCT 642
G-CSF after allogeneic HCT 644
Summary: clinical use of G-CSF after HCT 645
Granulocyte-macrophage colony-stimulating factor 645
GM-CSF after autologous HCT 645
GM-CSF after allogeneic HCT 645
Summary: clinical use of GM-CSF after HCT 646
Other hematopoietic growth factors and cytokines 646
Interleukin-3 646
Stem cell factor 646
Thrombopoietin/megakaryocyte growth factor 646
Interleukin-11 646
Cytokines and growth factors for immunotherapy after transplantation 647
GM-CSF for immunotherapy after transplantation 647
Interleukin-2 647
Keratinocyte growth factor 648
KGF in autologous HCT 648
KGF in allogeneic HCT 648
Conclusion 648
References 649
Chapter 44 Hematopoietic Cell Transplantation from Human Leukocyte Antigen Partially Matched Related Donors 652
Introduction 652
Donor selection 652
Function and polymorphism of HLA 652
HLA haplotypes and segregation in families 653
Donor and recipient matching 653
Donor-specific antibodies 654
Probability of identifying an HLA partially compatible family donor 654
Transplantation of T-replete marrow grafts 655
GVHD prophylaxis with methotrexate, calcineurin inhibitors, or both 655
Pre-transplantation alemtuzumab 655
Pre-transplantation polyclonal anti-T-cell therapy, PBPC, and post-transplantation mycophenolate mofetil 655
Post-transplantation, high-dose CY 658
Graft failure with T-cell-replete marrow 658
Immune reconstitution 659
Graft-versus-leukemia effect 659
Making a choice among stem cell sources 660
Transplantation of T-cell-depleted hematopoietic cell grafts 660
Risk of graft failure with T-cell-depleted marrow 660
Partial marrow T-cell depletion 660
Hematopoietic cell dose and use of PBPCs 661
Harnessing immunity to infections and leukemia 662
Role of NK cell alloreactivity in HLA-incompatible HCT 664
Conclusion 667
References 668
Chapter 45 Hematopoietic Cell Transplantation from Unrelated Donors 672
Introduction 672
Patient factors 672
Acute myeloid leukemia 673
Acute lymphoid leukemia 674
Myelodysplastic syndrome 674
Transplant factors 674
Product factors 674
Donor factors 674
The unrelated donor search process 675
Donor selection 676
New frontiers: the clinical importance non-HLA gene polymorphisms 678
Ethnicity and race 678
HLA haplotypes 678
KIR 680
Conclusion 683
References 684
Section 5 Hematopoietic Cell Transplantation for Aplastic Anemia 688
Chapter 46 Hematopoietic Cell Transplantation for Aplastic Anemia 688
Epidemiology 688
Clinical description 688
Etiology 688
Molecular and clinical biology 688
Hematopoietic cell transplantation 689
Syngeneic grafts 689
HLA-identical related bone marrow transplantation (BMT) 689
Graft rejection 689
Mixed donor–host hematopoietic chimerism 693
Acute graft-versus-host disease (see Chapter 83) 693
Chronic graft-versus-host disease (see Chapter 84) 694
Interstitial pneumonia 695
Survival 695
Transplantation for older patients 697
Influence of etiology of aplastic anemia on the outcome of marrow grafts 698
Late effects 699
Newer reduced-intensity conditioning regimens (see Chapter 21) 700
Non-transplant approaches 705
Comparison of immunosuppressive therapy and hematopoietic cell transplantation 706
Conclusion 707
References 708
Chapter 47 Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria 712
Introduction 712
Pathogenesis of PNH 712
The PIG-A gene mutation 712
PNH clonal evolution 712
Clinical manifestations 713
Classifications 713
Hemolysis 713
Nitric oxide scavenging 713
Thrombophilia 713
Association with AA, MDS 713
Natural history and prognosis 714
Diagnosis 714
Non-transplant treatment of PNH 714
Eculizumab 715
Corticosteroids 715
Androgens 715
Iron replacement 715
Transfusion 715
Transplantation for PNH 715
Transplants following reduced-intensity conditioning 718
Use of eculizumab during HCT 718
Autologous transplantation for PNH 719
Conclusion 719
References 720
Chapter 48 Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia 722
Introduction 722
The past: allogeneic hematopoietic cell transplantation as curative therapy in CML 722
Phase of disease 722
Ablative preparative regimens 723
Reduced-intensity conditioning (RIC) in CML 723
Donor type 724
Source of hematopoietic stem cells 724
Patient age 724
Relapse following transplantation 724
Graft-versus-leukemia effect in CML 724
Monitoring minimal residual disease 724
Treatment of post-transplant relapse 725
Autologous transplantation 725
The Present: TKI therapy and the more limited role of transplantation 727
Front-line TKIs in newly diagnosed CML 727
Second-line TKI therapy after imatinib failure or intolerance 727
Monitoring disease response to TKIs 728
Who and when do we transplant? 729
Should we ever offer transplantation as a first option? 729
When should transplantation be used after initial TKI failure? 729
Does prior treatment with TKIs affect transplant results? 729
The future of CML treatment 730
References 731
Chapter 49 Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia 734
Introduction 734
Classification and epidemiology 734
Clinical presentation and differential diagnosis 734
JMML in neurofibromatosis type 1 735
Myeloproliferation and JMML in Noonan syndrome and related rasopathies 735
Hematologic features 735
Chromosomal abnormalities 736
Molecular pathogenesis 736
Dominant somatic mutations of KRAS and NRAS 736
Germline mutations in NF1 and loss of heterozygosity 737
Dominant somatic mutations in PTPN11 737
Germline CBL mutations and loss of heterozygosity 737
Secondary mutations 737
Natural course and prognostic factors 737
Non-transplant approaches 738
Therapy targeting Ras-dependent pathways 738
Hematopoietic cell transplantation 739
Early experiences 739
Preparative regimen 739
Non-relapse mortality 739
Relapse 740
Graft-versus-host-disease and graft-versus-leukemia-effect 740
Stem-cell source and umbilical cord blood transplantation 741
Chimerism studies and MRD 741
Donor lymphocyte infusion 741
Second transplantation 741
Splenectomy and other treatment prior to transplantation 742
Outlook 742
References 743
Chapter 50 Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia 746
Introduction 746
Epidemiology and etiology 746
Molecular and cellular biology 746
Cell of origin 746
Pathology 747
Immunophenotype 747
Molecular pathology and cytogenetics 747
Classification 748
Clinical and laboratory presentation 749
Non-transplant approach to treatment 749
Remission induction 749
Postremission chemotherapy 749
Chemotherapy for recurrent AML 750
The special case of APL 750
Hematopoietic cell transplantation 750
Indications for allogeneic HCT in AML 750
HCT-specific issues 753
Relapse following HCT 756
HCT for APL 757
Conclusion 757
References 759
Chapter 51 Hematopoietic Cell Transplantation for Childhood Acute Myeloid Leukemia 761
Introduction 761
Epidemiology/classification/molecular and cellular biology 761
Karyotypic alterations 762
Somatic mutations 763
The role of HCT in CR1 AML 764
Autologous versus allogeneic versus chemotherapy approaches 764
Risk-based therapy in CR1 AML: current role of allogeneic HCT 764
The role of allogeneic HCT in CR2 + AML 765
A limited role for autologous HCT in CR2 AML 766
Outcomes of children undergoing HCT with AML not in remission 766
Pre-HCT MRD positivity: effect on survival 767
The role of HCT in acute promyelocytic leukemia 767
The role of HCT in therapy-related AML 768
Effect of hematopoietic cell source on outcomes 768
Related versus unrelated donors for children with AML 768
T-cell depletion of matched related or unrelated donors in AML 769
Cord blood outcomes in children with AML 769
Haploidentical approaches to children with AML 769
Preparative regimens for pediatric AML patients 769
Reduced-intensity conditioning (RIC) regimens in pediatric AML 770
The graft-versus-leukemia (GVL) effect in pediatric AML 770
Relapse after HCT 771
Immunologic interventions to treat AML relapsed after HCT 771
Second HCT 771
Conclusions – targeted chemotherapeutic, HCT, and cellular approaches to pediatric AML 772
References 773
Chapter 52 Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Adults 776
Introduction 776
Etiology 776
Signs and symptoms of disease 776
Clonal origin of leukemic lymphoid cells 776
Lineage-specific features of leukemic lymphoblasts 777
Mature B-cell ALL 777
Pre-B- and early pre-B-cell ALL 777
T-cell acute lymphoblastic leukemia 777
Mixed-lineage leukemia (ambiguous lineage) 777
Cytogenetic and molecular genetic analyses 777
Treatment of ALL in adults 778
CNS prophylaxis 778
Management of CNS prior to HCT 779
Maintenance therapy 779
Treatment of Philadelphia chromosome ALL 779
Prognostic factors in ALL 780
Role of minimal residual disease 780
Allogeneic HCT in first complete remission of ALL 780
Postremission therapies: matched-sibling HCT versus chemotherapy or autologous HCT 780
HCT for Philadelphia chromosome-positive ALL 782
Relapsed or primary refractory ALL 783
Unrelated donor HCT for ALL 784
Role of GVL effect in patients with ALL 784
HCT after reduced-intensity conditioning for treatment of ALL 784
Regimen development for allogeneic HCT for ALL 785
Management of relapse after allogeneic transplant for ALL 785
Autologous HCT for adult ALL 785
Cell sources for HCT 785
Umbilical cord transplantation 785
Haploidentical transplantation 786
Treatment strategy for ALL 786
Future considerations 787
References 788
Chapter 53 Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Children 790
Introduction 790
Diagnosis and classification of ALL in childhood 790
Biologic differences between pediatric and adult ALL 791
Outcome of sibling donor transplantation in children with ALL 792
Transplantation in first remission 792
Outcomes of transplantation in second or subsequent remission 794
Selection of conditioning regimens 795
Alternative donor HCT for children with ALL 797
Mismatched family member transplantations in children with ALL 797
Unrelated donor HCT 798
UCB transplantation for children with ALL 799
Autologous transplantation for children with ALL 800
Special pediatric considerations 800
Transplantation of infants with ALL 800
Transplantation of children with Down syndrome and ALL 800
Role of second transplant procedures for relapse 801
Conclusion 801
References 803
Chapter 54 Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms 808
Introduction 808
General considerations for hematopoietic cell transplantation in patients with MDS and MPN 808
Myelodysplastic syndromes 809
Presentation and terminology 809
Classification systems 809
Transplantation specific risk assessment 810
Non-transplant therapy and the decision on transplantation 810
Allogeneic transplantation 810
Secondary/treatment-related MDS 813
The search for the ideal regimen 814
MDS in children 814
Myeloproliferative neoplasms 815
The scope of MPN, presentation, and staging 815
Non-transplant therapy 816
Transplantation for PMF, PV, and ET 816
Other MPNs 817
Myelodysplastic/myeloproliferative neoplasms 817
Chronic myelomonocytic leukemia 817
Atypical CML 818
Juvenile myelomonocytic leukemia 818
Systemic mastocytosis 818
Autologous HCT 818
Relapse after HCT 818
GVHD 819
Conclusions and perspective 819
References 820
Chapter 55 Hematopoietic Cell Transplantation for Multiple Myeloma 823
General aspects of myeloma 823
Epidemiology and etiology of myeloma 823
Molecular and cellular biology 823
Clinical description 823
Staging, prognosis, and response 824
Myeloma therapy 825
Importance of achieving a complete response 825
Therapeutic approaches for SCT-eligible patients 825
Autologous stem-cell transplantation for myeloma 826
Patient selection 828
Stem-cell source 828
Current role of autologous HCT in myeloma 828
The emerging role of maintenance therapy post-SCT 829
Role of consolidation post-SCT 830
Autologous SCT as salvage therapy 831
Future directions for autologous HCT in myeloma 831
Allogeneic HCT in myeloma 831
Alternative donor HCT 832
Future directions for allogeneic HCT in myeloma 833
Conclusion 833
References 835
Index 838
Supplemental Images 876
Volume 2 907
Title Page 906
Copyright Page 907
Contents 910
Contributors 914
Preface to the First Edition 920
Tribute 922
Chapter 56 Hematopoietic Cell Transplantation for Hodgkin Disease 936
Epidemiology and etiology 936
Molecular and clinical biology 936
Clinical description 936
Non-transplant approaches 936
Hematopoietic cell transplantation 937
Results of autologous hematopoietic cell transplantation 937
Prognostic factors 938
Pre-transplant “debulking” chemotherapy 939
Pre-transplant radiation therapy 940
Post-transplant therapy 940
Functional imaging 941
Timing of transplantation 942
Autologous hematopoietic cell transplantation for children 944
Transplantation for elderly patients 945
Transplantation for HIV-associated Hodgkin disease 945
Late events 945
Management of relapse 946
Source of hematopoietic cells 947
Allogeneic hematopoietic cell transplantation 947
High-dose therapy regimens 951
Summary and future directions 952
References 953
Chapter 57 Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma (B Cell) 957
Introduction 957
Diffuse large B-cell lymphoma 957
Autologous HCT 957
Autologous HCT for DLBCL – relapsed disease 958
Allogeneic HCT for DLBCL 959
Double hit lymphoma 960
HCT for double hit lymphoma – relapsed disease 960
Mantle cell lymphoma 960
Front-line application of Autologous HCT 961
Autologous transplant for relapsed disease 962
Allogeneic HCT 962
Follicular lymphoma 962
Autologous HCT for follicular lymphoma 962
Allogeneic HCT for follicular lymphoma 963
Reduced-intensity allogeneic HCT 963
Novel conditioning regimens 964
Maintenance therapy after HCT 964
HCT for transformed lymphoma 965
Burkitt lymphoma 965
Lymphoblastic lymphoma 966
Involved field radiotherapy after HCT 966
Conclusion 967
References 968
Chapter 58 Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma (T Cell) 971
Introduction 971
Diagnosis and treatment of T-cell NHL 971
PTCL-nos excluding CTCL and NK/T-cell lymphomas 971
NK/T-cell lymphoma nasal and extranasal type 972
CTCL and Sézary syndrome 972
HCT for systemic or peripheral NK/T-cell lymphoma (PTCL) 973
Autologous HCT 973
Allogeneic HCT for PTCL 975
HCT for cutaneous T-cell lymphoma (CTCL) 978
Autologous HCT 978
Allogeneic HCT 978
Conclusion and future directions 980
References 982
Chapter 59 Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia 985
Introduction 985
Epidemiology 985
Etiology 985
Clinical presentation, diagnosis, and staging 986
Prognostic markers 986
Markers of CLL tumor burden 986
Cytogenetic prognostic markers 987
IGH gene mutation status 987
CD38 and ZAP-70 expression 987
Response criteria 988
Minimal residual disease – methods for monitoring depth of treatment response 988
Initial CLL therapy 988
Clinical challenges in advanced and high-risk CLL 989
Historical experience with autologous transplantation 989
Allogeneic transplantation 991
Special donor considerations in allogeneic transplantation for CLL 991
Allogeneic HCT with myeloablative conditioning 991
Reduced-intensity conditioning for CLL allogeneic HCT 992
Allogeneic HCT for CLL: patient selection 993
Treatment of post-transplant relapse 993
Novel agents in CLL 994
Cell therapy 994
Conclusion 994
References 995
Chapter 60 Autologous Hematopoietic Cell Transplantation for Systemic Light Chain (AL?) Amyloidosis 998
Introduction 998
Epidemiology 999
Pathogenesis 1000
Diagnosing AL-amyloidosis 1001
Clinical presentations 1002
Heart 1002
Kidneys 1003
Liver and gastrointestinal tract 1003
Peripheral nervous system 1003
Respiratory tract 1004
Hemostasis 1004
Prognosis and eligibility for HCT at diagnosis 1004
Therapy 1004
Efficacy and end-points 1004
Overview 1006
Hematopoietic stem-cell transplantation for AL-amyloidosis 1008
Mobilization and immune reconstitution 1010
Peri-transplant management 1011
Relapse 1012
Conclusion 1012
References 1013
Chapter 61 Autologous Hematopoietic Cell Transplantation for Breast Cancer and Germ?cell Tumors 1016
Introduction 1016
Hematopoietic cell transplantation for breast cancer 1016
High-dose chemotherapy trials in metastatic breast cancer 1016
High-dose chemotherapy in high-risk primary breast cancer (HRPBC) 1017
Prognostic factors of benefit from HDC 1019
Conclusions 1019
Germ-cell tumors 1021
HDC for refractory/relapsed NSGCT 1021
Can we predict the outcome of patients with relapsed GCT receiving HDC? 1022
Randomized trials of HDC in the salvage setting 1023
Other areas of uncertainty 1023
First-line HDC for poor-risk NSGCT 1023
Special considerations 1024
Surgical management after HDC 1024
Management of relapse post-HDC 1024
Conclusion 1024
References 1025
Chapter 62 Hematopoietic Cell Transplantation for Renal Cell Carcinoma and Other Solid Tumors 1028
Introduction 1028
Allogeneic transplantation as immunotherapy: the GVT effect 1028
The immune system and solid tumors 1028
Solid tumors as a GVT target 1029
Animal models exploring graft-versus-solid tumor effects 1029
Early clinical data suggesting GVT effects against solid tumors in humans 1029
Use of reduced-intensity conditioning in allogeneic transplantation for solid tumors 1030
Clinical results of reduced-intensity allogeneic HCT transplantation in solid tumors 1030
RCC: the National Institutes of Health experience 1030
Emerging role of RIC HCT for RCC 1034
Toxicities and limitations of RIC HCT in metastatic RCC 1035
RIC HCT in melanoma 1035
RIC HCT in other solid tumors 1036
Mechanisms underlying GVT effects in solid tumors 1037
Future directions 1038
References 1040
Chapter 63 Hematopoietic Cell Transplantation for Neuroblastoma 1042
Introduction 1042
Clinical presentation and staging 1042
Tumor molecular biology 1042
Risk classification and treatment approach 1043
Treatment of high-risk neuroblastoma 1043
Induction therapy 1043
Local control 1044
Autologous hematopoietic cell rescue 1044
Non-randomized comparisons of autologous HCT with chemotherapy 1044
Randomized comparison of autologous HCT with standard-dose chemotherapy 1045
High-dose conditioning regimens 1046
Tandem transplants 1047
Targeted radionuclides as part of high-dose therapy 1047
Allogeneic transplantation 1047
Hematopoietic cell source and purging 1048
Minimal residual disease 1048
Acute and late complications of HCT in neuroblastoma 1049
Conclusion 1049
References 1050
Chapter 64 Hematopoietic Cell Transplantation for Other Pediatric Solid Tumors 1053
Introduction 1053
Chemosensitivity 1053
Dose–response 1053
Dose limiting myelotoxicity 1053
Indications and outcomes 1053
Ewing sarcoma family of tumors 1053
Rhabdomyosarcoma 1055
Wilms tumor 1057
Osteosarcoma 1059
Retinoblastoma 1060
Desmoplastic small round cell tumor 1061
HCT for other rare pediatric solid tumors 1062
Future directions 1063
Patterns of failure 1063
Regimens 1063
Hematopoietic cell grafts 1064
Immunotherapy 1065
Conclusion 1065
References 1066
Chapter 65 Hematopoietic Cell Therapy for Human Immunodeficiency Virus Infection 1070
Introduction 1070
The pathogenesis of HIV-1 infection and AIDS 1070
HIV-1 infection 1070
The HIV-1 reservoir 1071
Allogeneic transplantation in HIV/AIDS patients 1071
Autologous stem-cell transplantation in the AIDS patient with lymphoma 1072
AIDS-related lymphoma 1072
Salvage therapy for AIDS-related lymphoma using autologous HSCT 1072
Management of the AIDS patient during HSCT 1074
Conditioning for allogeneic HSCT in hematologic malignancy 1074
Conditioning for autologous HSCT in hematologic malignancy 1074
cART management during HSCT 1074
Fungal and GVHD prophylaxis in the HIV/AIDS patient after HSCT 1074
Gene therapy for HIV/AIDS 1075
Molecular basis for gene therapy of HIV/AIDS 1076
Molecular strategies for HIV-1 gene therapy 1076
Clinical trials of gene therapy for HIV-1 infection 1078
Clinical trials of gene therapy using hematopoietic stem cells 1078
Gene therapy with autologous HSPCs 1078
Gene therapy using CD4+ T cells 1079
Future directions of gene therapy for HIV/AIDS 1079
Conclusion 1080
References 1081
Chapter 66 Hematopoietic Cell Transplantation for Autoimmune Diseases 1083
Introduction 1083
Proposed mechanisms for autoimmunity and autoimmune diseases 1083
The genetics of autoimmune disease 1083
Preclinical models of autoimmunity and hematopoietic cell transplantation 1084
Outcomes in patients with autoimmune diseases transplanted for another primary disease 1085
High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for autoimmune diseases: clinical experience 1085
Patient selection 1085
Collection and processing of the hematopoietic cell graft 1085
High-dose immunosuppressive therapy regimens 1086
Immune reconstitution after a high-dose immunosuppressive therapy regimen 1087
Specific autoimmune diseases and hematopoietic cell transplantation 1087
Allogeneic hematopoietic cell transplantation for autoimmune diseases: clinical experience 1094
Conclusion 1094
References 1095
Chapter 67 Hematopoietic Cell Transplantation for Rare Hematologic Malignancies 1098
Introduction 1098
Rare myeloid malignancies 1098
Langerhans cell histiocytosis 1098
Systemic mastocytosis 1099
Hypereosinophilic syndrome 1099
Acute megakaryoblastic leukemia 1100
Acute erythroleukemia 1100
Chronic myelomonocytic leukemia 1101
Rare lymphoid malignancies 1102
Adult T-cell leukemia/lymphoma 1102
Natural killer cell neoplasms 1103
Mycosis fungoides and Sézary syndrome 1105
Angioimmunoblastic T-cell lymphoma 1105
Primary central nervous system lymphoma 1108
Blastic plasmacytoid dendritic cell neoplasm 1109
Other rare lymphoid malignancies 1109
References 1110
Chapter 68 Adoptive T-cell Therapy for Viral Disease in the Setting of Hematopoietic Cell Transplantation 1114
Introduction 1114
Common viral infections post-transplant 1114
Cytomegalovirus 1114
Epstein–Barr virus 1114
Adenovirus 1114
Varicella zoster 1115
BK virus 1115
HHV6 1115
Herpes simplex virus 1115
Respiratory viruses 1115
Prerequisites for T-cell therapy 1115
Choice of antigen 1115
Antigen presentation 1115
Expansion strategies 1115
Clinical results using immunotherapy targeting single viruses 1117
EBV 1117
CMV 1120
Adenovirus 1121
JC virus 1121
Clinical results using immunotherapies targeting multiple viruses 1121
Targeting CMV, EBV, and adenovirus 1121
Adenovirus/EBV 1121
CMV/adenovirus 1122
CMV and EBV 1122
Risk of alloreactivity 1122
CTLs for HSCT patients with virus-naïve donors 1122
Third-party EBV CTLs 1123
Cord blood-derived CTLs 1123
Conclusions and future directions 1123
References 1124
Chapter 69 Adoptive T-cell Therapy for Malignancy in the Setting of Hematopoietic Cell Transplantation 1126
Introduction 1126
History and rationale for adoptive T-cell transfer therapy 1126
Background 1126
Rationale 1126
Principles of T-cell transfer 1126
Strategies for T-cell culture and engineering 1127
Rationale 1127
Approaches for T-cell culture 1127
Approaches for T-cell engineering 1127
Clinical approaches in the setting of HSCT 1129
Tumor-infiltrating lymphocytes 1129
Cytotoxic T-lymphocyte (CTL) therapy 1129
Combination approaches using vaccines and adoptive T?cell transfer 1130
Synthetic biology with engineered T cells 1130
Rationale 1130
Strategies 1131
Clinical trials with CAR T cells 1131
First-generation CARs 1131
Second- and third-generation CARs 1131
CAR trials targeting B-cell malignancies 1131
Toxicity with CAR T cells 1132
Clinical trials with transgenic TCR-modified T cells 1132
Incorporating CAR and TCR T cells into stem-cell transplant regimens 1133
Strategies to use engineered T cells as a bridge to transplant 1133
Moving to the dark side: adoptive therapy with T regulatory cells 1134
Dose and scheduling issues 1134
Conclusions and future directions 1135
References 1136
Chapter 70 Relapse of Hematologic Malignancy After Allogeneic Hematopoietic Transplantation 1139
Mechanism of relapse post-transplant 1139
Chronic myeloid leukemia 1139
Acute myeloid leukemia and myelodysplastic syndrome (MDS) 1140
Acute lymphoblastic leukemia 1142
Lymphoid malignancies 1142
Multiple myeloma 1143
Prevention of relapse 1143
Conclusions and future directions 1144
References 1145
Section 6 Hematopoietic Cell Transplantation for Thalassemia 1148
Chapter 71 Hematopoietic Cell Transplantation for Thalassemia 1148
Introduction 1148
Epidemiology and etiology 1148
Molecular and clinical biology 1148
Clinical features 1149
Non-transplant approaches 1149
Hematopoietic cell transplantation (HCT) 1150
Preparatory regimens 1150
Stem cell sources 1151
Engraftment 1152
Transplant-related morbidity and mortality 1152
Clinical transplant experience 1152
Management of the ex-thalassemic patient after HCT 1157
The role of HCT in the treatment of thalassemia 1158
References 1159
Chapter 72 Hematopoietic Cell Transplantation for Sickle Cell Disease 1161
Introduction 1161
Epidemiology and etiology 1161
Molecular and cellular biology 1162
Clinical description 1164
Pain 1164
Pulmonary complications 1164
Stroke 1165
Therapeutic alternatives to HCT 1166
RBC transfusions and stroke prevention 1166
Hydroxyurea 1166
HCT for SCD 1167
Current indications for HCT 1167
Current results of HCT for SCD 1167
Conclusion 1173
References 1174
Chapter 73 Hematopoietic Cell Transplantation for Immunodeficiency Diseases 1177
Introduction 1177
Immunophenotypic and genotypic variants of severe combined immunodeficiency (SCID) 1177
Clinical features of SCID 1178
Early detection of SCID: the potential impact of prenatal diagnosis and newborn screening on transplant outcome 1179
HCT for SCID 1180
Unmodified HLA-matched related HCT 1180
Immune reconstitution following unmodified HLA-matched related marrow transplants 1181
Alternative donor transplants for SCID 1181
Umbilical cord blood cell (CBC) transplants for SCID 1186
In utero HCT for SCID 1187
Long-term complications in patients transplanted for SCID 1187
Transplantation for other combined immunodeficiency syndromes (CID) and life-threatening genetic disorders of lymphocyte development or function 1188
Purine nucleotide phosphorylase (PNP) deficiency 1190
Combined immune deficiencies associated with defective DNA repair 1190
Cartilage–hair hypoplasia (CHH) 1191
Combined immunodeficiencies with ectodermal dysplasia 1191
Dock 8-deficient hyper IgE syndrome 1191
CD40 ligand deficiency (X-linked hyper IgM syndrome) 1191
The bare lymphocyte syndromes (BLS) 1192
Familial hemophagocytic lymphohistiocytosis (HLH) 1192
X-linked lymphoproliferative diseases (X-LP) 1193
Autoimmune lymphoproliferative syndromes (ALPS) 1193
X-linked immune dysregulation, polyendocrinopathy and enteropathy syndrome (IPEX) 1193
Wiskott–Aldrich syndrome (WAS) 1193
HCT for Wiskott–Aldrich syndrome (WAS) 1194
Late complications in patients transplanted for Wiskott–Aldrich syndrome 1194
Conclusion 1194
References 1196
Chapter 74 Hematopoietic Cell Transplantation for Storage Diseases 1201
Introduction 1201
HCT for storage diseases 1201
Why does HCT work? 1201
History 1203
General considerations 1204
Mucopolysacharidoses (MPS) and mucolipidoses (ML) 1204
MPS disorders for which HCT can be beneficial: MPS I, MPS VI, and MPS VII 1207
Hurler (MPS IH), Hurler-Scheie (MPS IH/S), and Scheie syndromes (MPS IS) 1207
Maroteaux-Lamy syndrome (MPS VI) 1211
Sly syndrome (MPS VII) 1212
Mucolipidoses (ML) types II and III (I-cell disease and pseudo-Hurler polydystrophy) 1212
MPS disorders for which HCT is not beneficial: MPS II, MPS III, MPS IV 1212
Hunter syndrome (MPS II) 1212
Sanfilippo syndrome (MPS III) 1213
Morquio syndrome (MPS IV) 1214
Leukodystrophies and other white matter diseases 1214
X-linked adrenoleukodystrophy (X-ALD) 1214
Globoid cell leukodystrophy 1217
Metachromatic leukodystrophy 1219
Other white matter disorders 1220
Glycoprotein metabolic and miscellaneous disorders 1221
Fucosidosis 1221
Gaucher disease 1221
?-Mannosidosis 1222
Aspartylglucosaminuria 1222
Miscellaneous disorders 1223
Future directions 1225
References 1226
Chapter 75 Hematopoietic Cell Transplantation for Macrophage, Granulocyte and Osteoclast Disorders 1229
Introduction 1229
General considerations for HCT 1231
Timing of HCT 1231
Choice of donor for HCT 1231
Preparative regimens 1231
Macrophage disorders 1231
Hemophagocytic lymphohistiocytosis 1231
Granulocyte disorders 1234
Quantitative granulocyte disorders 1234
Qualitative neutrophil disorders 1237
Conclusion 1241
References 1242
Chapter 76 Hematopoietic Cell Transplantation for Fanconi Anemia 1245
Introduction 1245
Early history 1245
Clinical features 1245
Diagnosis 1249
The FA pathway and DNA repair 1250
Pathophysiology of marrow failure and leukemogenesis 1253
Somatic mosaicism 1253
Genotype–phenotype correlations 1255
Non-transplant treatment strategies 1255
Androgens 1255
Vitamins and antioxidants 1257
Hematopoietic growth factor therapy 1258
Supportive care 1258
Hematopoietic cell transplantation 1258
HLA-identical sibling donor HCT 1258
Alternative donor HCT 1260
Cancer risk after HCT 1262
Genetic counseling 1263
Future directions 1264
Gene therapy 1264
Stem cells and tissue repair 1265
Conclusion 1265
References 1266
Section 7 Complications of hematopoietic cell transplantation 1269
Chapter 77 Mechanisms and Treatment of Graft Failure 1269
Introduction 1269
Overview of trafficking, homing, and engraftment of HSCs 1269
Definitions 1269
Primary graft failure 1269
Secondary or late graft failure 1270
Graft rejection and poor graft function 1270
Mixed chimerism following allogeneic HCT 1270
Incidence of graft failure 1270
Causes of graft failure 1271
Immune-mediated graft rejection 1271
Histocompatibility antigens 1272
ABO match 1273
Additional factors that might influence graft failure risk 1273
Strategies for risk reduction of graft failure 1276
Monitoring of graft performance 1277
Interventions for graft failure 1277
Use of autologous back-up 1277
Use of growth factors after graft dysfunction 1277
Changes in immune suppression 1277
Use of donor lymphocyte infusion 1277
Use of CD34+ boost 1278
Regrafting 1278
Conclusion 1279
References 1280
Chapter 78 Blood Group Incompatibilities and Hemolytic Complications of Hematopoietic Cell Transplantation 1284
Introduction 1284
Hemolytic complications of ABO incompatibility 1284
Delayed hemolytic reactions 1285
Management of ABO and Rh incompatibility 1285
Treatment of pure red cell aplasia 1287
Hemolysis and thrombotic microangiopathy (TMA) syndrome 1287
Therapy for post-HCT TMA 1289
Conclusion 1289
References 1290
Chapter 79 Principles of Transfusion Support Before and After Hematopoietic Cell Transplantation 1292
Introduction 1292
Red blood cell components 1292
Red cells 1292
Leukocyte-reduced red cells 1292
Washed red cells 1292
Coagulation factor components 1293
Fresh frozen plasma 1293
Plasma (FP24) 1293
Cryoprecipitate and fibrinogen 1293
Blood group compatibility of components used to replace coagulation factors 1293
Platelet components 1293
Platelet concentrates prepared from whole blood 1293
Platelet concentrates prepared by apheresis 1294
Platelet storage conditions and duration 1294
Transfusion of platelets 1294
Treatment of active bleeding 1295
Dose of platelets and outcome of platelet transfusion 1295
ABO (H) and Rh in platelet transfusion 1295
Lack of response (refractoriness) to platelet transfusion 1296
Role of thrombopoietin in platelet transfusion 1297
Granulocyte concentrates and granulocyte transfusion 1298
Transfusion strategies in HCT 1298
Pre-transplantation 1298
Post-transplantation 1298
Transfusion prophylaxis for invasive procedures 1299
Prevention of transfusion-transmitted CMV infection 1299
Prevention of transfusion-associated GVHD 1299
Irradiation of blood components 1299
Storage of irradiated components 1300
Leukocyte reduction to prevent GVHD 1300
Pathogen inactivation and prevention of GVHD 1300
Irradiation of blood products for autologous bone marrow transplantation 1300
Non-cellular blood components 1300
Transfusion therapy for HCT donors 1300
Complications of blood transfusion 1300
Hemolytic transfusion reactions 1300
Febrile non-hemolytic transfusion reactions 1301
Allergic and anaphylactic reactions 1301
Pulmonary reactions: transfusion-related acute lung injury 1301
Reactions to platelet transfusions 1302
Reactions to granulocyte transfusions 1302
Other immunologic complications of transfusion 1302
Bacterial contamination of units 1302
Non-immunologic complications of blood transfusion 1303
Transfusion-transmitted diseases 1303
Conclusion 1306
Acknowledgment 1306
References 1307
Chapter 80 Vascular Access and Complications 1311
Introduction 1311
Indications and patient selection 1311
Catheter selection 1312
Peripherally inserted central venous catheter (PICC) 1313
Implantable subcutaneous ports 1313
Externally tunneled catheter 1313
Insertion site selection 1314
Insertion technique 1315
Catheter care 1316
Complications 1317
Complications related to catheter insertion 1317
Catheter-related complications 1319
Catheter removal 1324
References 1325
Chapter 81 Pharmacologic Prevention of Acute Graft-versus-Host Disease 1327
Historical development 1327
Pathogenesis 1327
Alloreactivity 1327
Predictive factors 1328
Non-specific immunosuppressive drugs 1329
Corticosteroids 1329
Methotrexate (MTX) 1331
Specific T-cell immunosuppressive drugs 1332
Cyclosporine (CSP) 1332
Tacrolimus (FK506) 1335
Sirolimus (rapamycin) 1335
Mycophenolate mofetil 1336
Cyclophosphamide 1337
Antibodies 1338
Anti-CD3 1338
Intravenous immunoglobulin (IVIg) 1338
Antithymocyte globulin 1338
Anticytokine therapy 1339
Alemtuzumab 1339
Other agents 1339
Induction of anergy 1339
Photopheresis/pentostatin 1340
Conclusion 1340
References 1341
Chapter 82 T-cell Depletion to Prevent Graft-versus-Host Disease 1344
Introduction 1344
Early preclinical models of T-cell depletion 1344
T-cell dose and GVHD 1344
Specificity of TCD 1345
Ex vivo negative selection TCD 1345
Ex vivo positive selection TCD 1346
Haploidentical donor TCD transplantation 1347
In vivo anti-T-cell antibody TCD 1347
In vivo TCD and reduced-intensity conditioning HCT 1348
Organ Dysfunction and TCD 1349
Engraftment and TCD 1349
Immune reconstitution and infectious complications after TCD HCT 1350
Disease relapse and TCD 1350
Novel approaches to graft manipulation 1351
Conclusion 1351
References 1352
Chapter 83 Manifestations and Treatment of Acute Graft-versus-Host Disease 1355
Background, definition, and incidence of acute graft-versus-host disease 1355
Incidence and staging 1355
Risk factors for acute GVHD 1355
Human leukocyte antigen disparity 1355
Hematopoietic stem-cell source and graft composition 1355
Donor–recipient clinical factors 1356
Non-HLA genetic factors 1357
Tolerance 1357
Conditioning regimen intensity and immunomodulation 1357
Microbial environment 1357
Clinical features of acute GVHD 1358
Cutaneous acute GVHD 1358
Gastrointestinal acute GVHD 1358
Hepatic acute GVHD 1358
Other findings 1358
Diagnosis and differential diagnosis 1358
Prediction and prognostication of acute GVHD 1359
Therapy of acute GVHD 1359
Primary therapy 1359
Secondary therapy 1360
Supportive care 1361
Special scenarios 1361
Hyperacute GVHD 1361
Autologous GVHD 1361
Transfusion-associated GVHD 1362
Conclusion 1362
References 1363
Chapter 84 Chronic Graft-versus-Host Disease – Clinical Manifestations and Therapy 1369
Introduction 1369
Risk factors for onset of chronic GVHD 1369
Risk factors associated with increased non-relapse mortality and inferior survival 1370
Risk factors associated with duration of therapy 1370
Pathogenesis in humans 1371
Diagnosis of cGVHD 1372
Organs in which the diagnosis may not be straightforward 1373
Organ severity staging of cGVHD 1379
Global severity staging of cGVHD 1380
Histopathology and diagnosis of cGVHD 1380
Management of cGVHD 1380
Prevention 1380
Treatment 1380
Graft-versus-leukemia effect 1385
Future directions 1386
Acknowledgments 1386
References 1387
Chapter 85 Bacterial Infections 1389
Introduction 1389
Biology of bacterial pathogens 1389
Antibiotic resistance 1390
Compromised host defenses 1391
Early recovery (phase I) 1391
Mid-recovery (phase II) 1392
Late recovery (phase III) 1392
Spectrum of bacterial infections 1393
Early recovery (phase I) 1393
Mid-recovery (phase II) 1394
Late recovery (phase III) 1394
Treatment strategies 1394
First fever during neutropenia 1394
Antibiotic modification during neutropenia 1397
Fever following resolution of neutropenia 1399
Outpatient management of neutropenia 1399
Vancomycin-resistant enterococci (VRE) 1399
Clostridium difficile-associated diarrhea (CDAD) 1400
MRSA and CA-MRSA 1402
Neutropenic enterocolitis/typhilitis 1403
Treatment of late bacterial infections 1403
Treatment of intravascular catheter-related infections 1403
Preventive strategies 1404
General measures 1404
Antibiotic prophylaxis during neutropenia 1404
Bacterial prophylaxis after engraftment 1405
Adjunctive measures 1405
Growth factors 1405
Granulocyte transfusions 1406
Immunobiologic agents 1406
Conclusion 1407
References 1408
Chapter 86 Fungal Infections After Hematopoietic Cell Transplantation 1414
Introduction 1414
Infections caused by Candida species 1414
Mycology and epidemiology 1414
Pathogenesis and immunity 1414
Clinical manifestations 1415
Diagnosis and therapy 1416
Infections caused by Aspergillus species 1418
Mycology and epidemiology 1418
Pathogenesis and immunity 1419
Clinical manifestations 1419
Diagnosis and therapy 1421
Less common fungi 1423
Pneumocystis jirovecii 1423
Other fungal infections 1424
Conclusion 1424
References 1426
Chapter 87 Cytomegalovirus Infection 1429
Introduction 1429
Clinical aspects of CMV infection 1429
Viral latency 1429
CMV epidemiology 1429
Prevention of CMV infection after HCT 1430
Preemptive treatment strategy for prevention of CMV after HCT 1431
General prophylactic treatment strategies for prevention of CMV after HCT 1431
Specific issues in CMV infection prevention 1431
CMV-associated diseases after HCT 1432
Diagnosis of CMV-associated infection and disease 1432
CMV-associated pneumonitis 1433
CMV-associated enteritis and other organ-specific diseases 1433
Other CMV-associated syndromes 1434
Treatment of CMV-associated diseases 1434
Therapy of CMV-associated interstitial pneumonia (CMV?IP) 1434
Therapy for CMV-associated enteritis and other syndromes 1434
Complications of CMV therapy 1434
Cellular Immunity to CMV 1435
Innate immunity 1435
T-cell immunity 1436
Future developments relating to CMV infection in HCT 1436
CMV infection and protection from leukemic relapse 1436
Improved antiviral agents for CMV 1436
CMV vaccines 1437
T-cell Immunotherapy for CMV infection 1437
Conclusion 1437
References 1438
Chapter 88 Herpes Simplex Virus Infections 1440
Introduction 1440
Virology 1440
Pathogenesis 1440
Immunology 1441
General aspects 1441
Immune evasion 1441
Immunology in HCT 1441
Epidemiology 1441
Clinical manifestations 1442
Oropharyngeal/orofacial infection 1442
Genital/perianal infection 1443
Gastrointestinal infection 1443
Respiratory infection 1443
Central nervous system 1444
Other syndromes 1444
Diagnosis 1444
Management of HSV infection in HCT 1445
Prophylaxis 1446
Conclusion 1446
References 1447
Chapter 89 Varicella Zoster Virus Infections 1449
Introduction 1449
The virus 1449
Epidemiology 1449
Primary VZV infection 1449
Recurrent VZV infection 1450
Reinfection with VZV 1451
Mechanisms of pathogenesis and viral immune evasion 1452
Primary VZV infection 1452
Recurrent VZV infection 1454
Viral immune evasion 1455
The host response 1455
Clinical manifestations 1457
Primary VZV infection 1457
Recurrent VZV infection 1458
Laboratory diagnosis 1460
Viral isolation in tissue culture cells 1460
Direct detection of VZV antigens in infected cells by immunofluorescence 1461
Viral DNA detection 1461
Serologic diagnosis 1461
Antiviral therapy for VZV infection 1462
Acyclovir 1462
Other antiviral compounds 1463
Anti-VZV drugs in development 1464
Treatment of PHN 1464
Prophylaxis for VZV infection 1465
Varicella zoster immune globulin 1465
Acyclovir prophylaxis 1465
VZV vaccines 1467
Conclusion 1468
References 1469
Chapter 90 Epstein–Barr Virus Infection 1475
Introduction 1475
Aspects of EBV biology 1475
EBV-associated diseases 1476
EBV-associated tumors 1476
Allogeneic HCT and EBV-PTLD risk factors 1477
EBV-PTLD presentation and diagnosis 1478
EBV monitoring 1478
Treatment and prevention 1478
EBV-associated non-neoplastic diseases 1478
EBV-PTLD 1478
Treatment of other EBV-associated tumors 1480
Conclusion 1481
References 1482
Chapter 91 Respiratory Viruses After Hematopoietic Cell Transplantation 1484
Introduction 1484
Respiratory syncytial virus 1484
Clinical significance 1484
Risk factors 1484
Treatment and prevention 1484
Human metapneumovirus 1489
Clinical significance 1489
Risk factors 1489
Prevention and treatment 1489
Parainfluenza viruses 1489
Clinical significance 1489
Risk factors 1489
Treatment and prevention 1490
Influenza viruses 1490
Clinical significance 1490
Risk factors 1490
Treatment and prevention 1490
Human rhinoviruses 1491
Clinical significance 1491
Risk factors 1491
Treatment and prevention 1491
Human coronaviruses 1492
Clinical significance 1492
Risk factors 1492
Treatment and prevention 1492
Human bocavirus 1492
Clinical significance 1492
Risk factors 1492
Treatment and prevention 1492
WU and KI polyomaviruses 1492
Clinical significance 1492
Risk factors 1492
Treatment and prevention 1493
Measles virus 1493
Clinical significance 1493
Risk factors 1493
Treatment and prevention 1493
Conclusions and future perspective 1493
Acknowledgments 1493
References 1494
Chapter 92 HHV-6A, HHV-6B, HHV-7, and HHV-8 After Hematopoietic Cell Transplantation 1498
Introduction 1498
Human herpesviruses 6A and 6B 1498
Epidemiology and basic virology 1498
Chromosomal integration of HHV-6 (CIHHV-6) 1499
Diagnosis of HHV-6 infection 1499
Clinical manifestations in HCT patients 1500
HHV-6 encephalitis 1501
Management of HHV-6 infections 1503
Human herpesvirus-7 1503
Epidemiology and basic virology 1503
Clinical manifestations in HCT patients 1503
Human herpesvirus-8 1503
Epidemiology and basic virology 1503
Clinical manifestations in HCT patients 1503
Conclusion and future development 1504
References 1505
Chapter 93 Human Adenovirus, Polyomavirus, and Parvovirus Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation 1508
Introduction 1508
Human adenovirus 1508
Epidemiology 1508
Virologic aspects 1508
Diagnostic methods 1509
Clinical manifestations 1510
Treatment 1511
Prevention 1511
Human polyomaviruses 1512
Epidemiology 1512
Virologic aspects 1512
Diagnostic methods 1513
Clinical manifestations 1513
Treatment 1516
Prevention 1517
Human parvovirus 1517
Epidemiology 1517
Virologic aspects 1517
Diagnostics 1517
Parvovirus B19 disease 1518
Treatment 1518
Prevention 1518
References 1519
Chapter 94 Gastrointestinal and Hepatic Complications 1523
Introduction 1523
Evaluation of intestinal and liver problems before transplant 1523
Ulcers, tumors, and infections in the gastrointestinal tract 1523
Diarrhea 1523
Perianal pain 1524
Liver disease in donors and recipients 1524
Gall bladder and bile duct stones 1525
Problems from transplant through the first year 1525
Nausea, vomiting, and anorexia 1525
Conditioning therapy 1525
Upper gut GVHD 1525
Infection 1526
Medications 1526
Jaundice, hepatomegaly, and abnormal liver tests 1526
Sinusoidal obstruction syndrome (SOS) 1526
Cholestatic disorders: cholangitis lenta, acute GVHD, and drug-induced liver injury 1528
Acute hepatitis 1529
Fungal and bacterial infections 1529
Gall bladder and biliary disease 1529
Malignant disorders 1530
Idiopathic hyperammonemia and coma 1530
Gastrointestinal bleeding 1530
Dysphagia, painful swallowing, and esophageal pain 1530
Diarrhea 1531
Abdominal pain 1532
Perianal pain 1534
Problems in long-term transplant survivors 1534
Gastrointestinal problems 1534
Liver diseases 1535
Gallbladder and biliary diseases 1537
Pancreatic disease 1537
Systemic iron overload 1537
References 1539
Chapter 95 Lung Injury Following Hematopoietic Cell Transplantation 1544
Introduction 1544
Diagnostic considerations and role of bronchoalveolar lavage 1544
Infectious lung injury 1545
Non-infectious, acute lung injury 1546
Chemotherapy-associated pneumonitis 1546
Transfusion-related acute lung injury (TRALI) 1546
Idiopathic pneumonia syndrome (IPS): definition, clinical course, and spectrum of disease 1546
Non-infectious, late-onset lung injury: obstructive and restrictive lung disease 1552
Definition, risk factors, and clinical course 1552
Restrictive lung disease 1552
Obstructive lung disease/bronchiolitis obliterans (BO) 1552
Pathogenesis of chronic lung injury 1553
Treatment of chronic lung injury after HCT 1555
Optimizing the management of patients with chronic pulmonary dysfunction 1555
Conclusion 1557
References 1558
Chapter 96 Kidney and Bladder Complications of Hematopoietic Cell Transplantation 1561
Introduction 1561
Acute kidney injury 1561
Epidemiology 1561
Risk factors for AKI by type of conditioning regimen and transplant 1561
Pathogenesis of AKI after HCT 1562
Management of AKI 1563
Chronic kidney disease 1563
Epidemiology 1563
Clinical syndromes of CKD after HCT 1564
Nephrotic syndrome 1566
GVHD-related CKD 1566
Treatment of TMA and GVHD-related CKD 1568
Bladder complications after HCT 1569
Hemorrhagic cystitis 1569
Conclusion 1571
Acknowledgment 1571
References 1572
Chapter 97 Endocrine Complications Following Hematopoietic Cell Transplantation 1576
Introduction 1576
Hypothalamic–pituitary dysfunction 1576
Growth disorders 1576
Evaluation of growth disorders post-HCT 1577
Management of growth disorders post-HCT 1578
Dysfunctional bone metabolism and osteoporosis 1579
Evaluation of metabolic bone dysfunction post?HCT 1580
Management of metabolic bone dysfunction post?HCT 1580
Vitamin D deficiency 1581
Thyroid dysfunction 1581
Functional derangement of the thyroid post-HCT 1583
Mass lesions of the thyroid post-HCT 1584
Metabolic and electrolyte abnormalities 1586
Abnormal water metabolism 1587
Carbohydrate and lipid abnormalities 1590
Adrenal dysfunction 1591
Evaluation of adrenal dysfunction post-HCT 1592
Management of adrenal dysfunction post-HCT 1593
Gonadal dysfunction 1593
Male 1594
Female 1596
Sexual dysfunction 1598
Male 1598
Female 1599
Conclusion 1600
Chapter 98 Common Potential Drug Interactions Following Hematopoietic Cell Transplantation 1603
Introduction 1603
P-glycoprotein (P-gp) system 1603
Organic Anion-Transporting Polypeptide (OATP) system 1603
Cytochrome P450 (CYP450) isoenzyme system 1604
Uridine 5'-diphosphate glucuronosyltransferase (UGT) enzyme system 1604
Azole antifungals 1604
Fluconazole 1604
Itraconazole 1605
Voriconazole 1605
Posaconazole 1606
Echinocandins 1606
Immunosuppressants 1607
Calcineurin inhibitors 1607
Mycophenolic acid (MPA) derivatives 1608
Sirolimus 1609
Chemotherapy 1610
Busulfan 1610
Cyclophosphamide 1610
Tyrosine kinase inhibitors (TKIs) 1610
Statins 1612
Therapeutic drug monitoring (TDM) 1612
Conclusion 1612
References 1613
Chapter 99 Nutrition Support of the Hematopoietic Cell Transplant Recipient 1615
Introduction 1615
Nutrition assessment 1615
Pre-transplant assessment 1615
Nutrition history 1615
Anthropometry 1615
Biochemical indices 1615
Other assessment tools 1615
Impact of body weight 1616
Integrative medicine 1616
Nutrient and fluid requirements 1616
Nutrition support 1616
Oral diet 1616
Enteral nutrition 1617
Parenteral nutrition 1619
Glutamine-enriched nutrition support 1620
Special management problems 1620
Oral/gastrointestinal issues 1620
Sinusoidal obstructive syndrome 1620
Renal complications 1620
Pulmonary compromise 1622
Iron overload 1622
Glucocorticoid-induced diabetes 1622
Acute graft-versus-host disease 1622
Long-term complications and management 1623
Chronic graft-versus-host disease 1623
Growth and development issues 1623
Metabolic syndrome 1623
Osteoporosis and alterations in vitamin D status 1623
Conclusion 1623
References 1624
Chapter 100 Pain Management 1626
Introduction 1626
Anatomy and physiology of pain 1626
Ascending nociceptive systems 1626
Modulation of nociceptive traffic 1626
The clinical phenomenon of pain 1626
What is pain? 1627
Pain and suffering in the HCT patient 1627
Assessment of pain and treatment efficacy 1628
History 1628
Pain measurement and monitoring 1628
Pain scales 1628
Ability to function 1629
Medication use and side effects 1629
Pain diagnostics and therapy selection 1629
Treating the patient with difficult pain management problems 1629
Non-pharmacologic techniques in pain management 1629
Mechanisms of non-pharmacologic techniques 1629
Information 1630
Education 1630
Other cognitive–behavioral strategies 1631
Pediatric considerations 1631
Non-opioid pharmacologic management of pain 1631
NSAIDs and acetaminophen 1631
Antidepressants 1632
Opioids in the management of pain 1632
Opioid pharmacology 1633
Opioid pharmacokinetics 1633
Opioid pharmacodynamics 1633
Opioid side effects 1633
Opioid tolerance and dependence 1634
Opioids commonly used in the HCT patient 1635
Opioid use in clinical practice 1636
Opioid tapering 1637
Clinical pain management in the HCT patient 1638
Pre transplant 1638
In-hospital, peri-transplant period 1638
Pseudoaddiction 1638
Patients with prior history of substance abuse 1638
Postengraftment 1639
Neuropathic pain 1640
Pain due to diagnostic or therapeutic maneuvers 1640
Analgesia/sedation for painful and unpleasant procedures 1641
Non-pharmacologic management of procedures 1641
Pharmacologic management of procedures 1641
Invasive analgesic techniques in the HCT patient 1642
Analgesia and sedation in dying patients 1642
Conclusion 1642
References 1643
Chapter 101 Oral Complications of Hematopoietic Cell Transplantation 1646
Introduction 1646
Correlations with the phases of transplantation 1646
Pre-transplantation oral evaluation and stabilization 1646
Dental treatment 1646
Prophylactic antibiotics 1648
Post-HCT oral complications 1649
Oral care protocols 1649
Patient education 1650
Oropharyngeal mucositis (OM) 1650
Oral infections 1653
Oral hemorrhage 1655
Salivary gland hypofunction 1655
Oral GVHD 1655
Taste dysfunction 1656
Neurotoxicity, neuropathies, and orofacial pain 1656
Reduced-intensity conditioning regimen for HCT transplantation 1656
Evaluations for cGVHD: oral assessments 1658
Antiosteoclastic therapy-associated osteonecrosis of the jaws 1658
mTOR inhibitor oral ulcerations 1658
Routine dental care guidelines post-HCT 1659
Orofacial/dental growth and development 1659
Second malignancy post-HCT 1659
Conclusion 1660
References 1661
Chapter 102 Growth and Development After Hematopoietic Cell Transplantation 1663
Introduction 1663
Thyroid function 1663
Preparative regimens consisting of chemotherapy only 1664
Preparative regimens containing irradiation 1664
Treatment 1665
Growth 1665
Preparative regimens containing chemotherapy 1666
Radiation-containing preparative regimens 1667
Puberty 1668
Preparative regimens containing only chemotherapy 1669
Preparative regimens containing radiation 1669
Conclusion 1670
References 1672
Chapter 103 Delayed Non-malignant Complications After Hematopoietic Cell Transplantation 1675
Introduction 1675
Cardiovascular risk factors and cardiac disease 1675
Recommendations for screening 1676
Delayed pulmonary complications 1676
Recommendations for screening 1677
Endocrine complications 1677
Recommendations for screening 1678
Fertility 1678
Osteonecrosis 1678
Recommendations for screening 1679
Chronic kidney disease 1679
Recommendations for screening 1679
Visual impairments 1679
Recommendations for screening 1679
Chronic disease burden after hematopoietic cell transplantation 1679
Late mortality 1680
Health behaviors of long-term survivors of hematopoietic cell transplantation 1681
Quality of life after hematopoietic cell transplantation 1681
Neuropsychologic wellbeing 1682
Long-term follow-up 1682
References 1684
Chapter 104 Subsequent Malignant Neoplasms After Hematopoietic Cell Transplantation 1686
Introduction 1686
MDS and AML after autologous HCT 1686
Clinicopathologic syndromes 1686
Risk factors for t-MDS/t-AML after HCT 1688
Pathogenesis of t-MDS/t-AML 1688
Outcome of patients with t-MDS/t-AML after autologous HCT 1691
Prediction of risk of t-MDS/t-AML 1692
Gene expression analysis 1692
Reducing risk of t-MDS/t-AML after autologous HCT 1692
Lymphomas 1692
Post-transplantation lymphoproliferative disorder 1692
Late-onset lymphoma 1694
Solid tumors 1694
Pathogenesis of solid tumors after HCT 1695
Treatment of patients with solid tumors after HCT 1696
Conclusion 1696
References 1698
Chapter 105 Neurologic Complications of Hematopoietic Cell Transplantation 1701
Introduction 1701
Infectious complications 1701
Cerebrovascular complications 1703
Metabolic complications 1704
Neurologic manifestations of recurrent disease 1705
Immune-mediated complications of the central nervous system: a real entity? 1706
Immune-mediated abnormalities of the peripheral nervous system 1706
Complications from the calcineurin inhibitors cyclosporine and tacrolimus 1707
Complications from other immunosuppressive drugs 1708
Complications from conditioning agents 1709
Complications from supportive care drugs 1709
Pre-transplantation neurologic screening 1710
References 1711
Chapter 106 Vaccination of Allogeneic and Autologous Hematopoietic Cell Recipients 1713
Introduction 1713
Scope of the problem 1713
Loss of humoral immunity and vaccination guidelines 1714
Immunogenicity of vaccines after HCT 1716
Pertussis 1716
Haemophilus influenzae and pneumococcal vaccines 1716
Meningococcus 1717
Influenza 1717
Hepatitis B 1718
Hepatitis A 1718
Measles, mumps, rubella, varicella zoster (VZ) 1718
Varicella/herpes zoster 1718
Other live vaccines 1719
Administration of live vaccines and isolation of household contacts given live vaccines 1719
Conclusion 1719
References 1721
Index 1723
Supplemental Images 1761
EULA 1775
| Erscheint lt. Verlag | 14.12.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Chirurgie |
| Medizinische Fachgebiete ► Innere Medizin ► Hämatologie | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie | |
| Schlagworte | Acute Lymphoblastic Leukemia in Adults • Acute Lymphoblastic Leukemia in Children • Adult Acute Myeloid Leukemia • allogeneic hematopoietic cell transplantation • Autoimmune diseases • Autologous Hematopoietic Cell Transplantation • Bone marrow • Childhood Acute Myeloid Leukemia • Chronic Myeloid Leukemia • Cord blood • Counseling • Cryopreservation • Donor Registries • Engraftable Hematopoietic Stem Cells • Ethical • Graft-versus-Host Disease • Hämatologie • Hämatologie • Hematology • Hematopoiesis • Hematopoietic Cell Procurement • hematopoietic stem cells • High-dose Chemotherapy • human pluripotent stem cells • Medical Science • Medizin • Mesenchymal Stromal Cells • minimal residual disease • natural killer cells • nursing • Peripheral Blood Cell Donors • Peripheral Blood Hematopoietic Cells • Psychosocial • radioimmunotherapy • Radiotherapeutic • Reduced-intensity Allogeneic Transplantation Regimens • Stem Cell Biology • stem cell transplantation • Transplant Program |
| ISBN-10 | 1-118-41612-0 / 1118416120 |
| ISBN-13 | 978-1-118-41612-9 / 9781118416129 |
| Informationen gemäß Produktsicherheitsverordnung (GPSR) | |
| Haben Sie eine Frage zum Produkt? |
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