Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation

By Joseph H. Antin and Frederick R. Appelbaum

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.

• Language: English
• Publisher: Wiley
• Release date: Dec 23, 2015
• ISBN: 9781118416075

Book preview

Table of Contents

Cover

Volume 1

Title Page

Contributors

Preface to the First Edition

Preface to the Fifth Edition

Tribute

List of Abbreviations

SECTION 1: History and Use of Hematopoietic Cell Transplantation

CHAPTER 1: A History of Allogeneic and Autologous Hematopoietic Cell Transplantation

How it all began

History of allogeneic HCT

History of autologous HCT

Conclusion

References

CHAPTER 2: Uses and Growth of Hematopoietic Cell Transplantation

Introduction

Changing indications for HCT

Changes in patient selection

Hematopoietic cell sources

Autologous transplantation

Allogeneic transplantation

Transplantation regimens and supportive care

Long-term survivors

Addressing barriers to use of HCT

Assessing and improving results of HCT

References

SECTION 2A: Scientific Basis or Hematopoietic Cell TransplantationHematopoiesis and Stem Biology Transplantation

CHAPTER 3: Generation of Definitive Engraftable Hematopoietic Stem Cells from Human Pluripotent Stem Cells

Introduction

Generation of HSCs from ESCs

Are PSC-derived hematopoietic progenitors capable of engraftment and hematopoietic repopulation?

Can we generate immunologically compatible HSCs?

Conclusion

References

CHAPTER 4: Hematopoietic Stem Cells, Regenerative Medicine, and Leukemogenesis

Introduction

Failure of hematopoietic cell transplanters and journals to use appropriate terms to describe the cells that are transplanted

History of the HSC

Properties of mouse HSCs and other MPPs

Lineage committed hematopoietic progenitor cells

Alternative developmental pathways

Gene expression profiles of HSCs and their oligolineage progenitors: Gene Expression Commons

Transplantation of HSCs in mouse and human

Graft engineering

The future of HSC transplantation: replacing myeloablative conditioning with selective depletion of endogenous HSCs and living donors with cell lines as donors

Conclusions

References

CHAPTER 5: Marrow Microenvironment and Biology of Mobilization of Stem Cells

Introduction

Stem cell homeostasis and the components of the bone marrow niche

Stem cell mobilization

Cellular mediators of G-CSF mobilization

HSPC mobilization via pharmacologic disruption of the CXCR4/CXCL12 axis

Other biologic factors involved in mobilization

Conclusion

References

CHAPTER 6: Expansion of Human Hematopoietic Stem Cells

Introduction

Initial attempts at ex vivo stem cell expansion for clinical application using cytokine-based expansion systems

Pre-clinical approaches for ex vivo HSPC expansion: intrinsic and extrinsic regulators of cell fate

Notch signaling in hematopoiesis

Clinical trials using ex vivo expanded/manipulated cord blood HSPC

Notch-mediated ex vivo expansion systems for clinical application

Other emerging approaches to ex vivo expansion

Alternative strategies to overcome the limiting cell dose in CB grafts: ex vivo modulation to enhance HSC homing

Conclusion

References

CHAPTER 7: Mesenchymal Stromal Cells and Hematopoietic Cell Transplantation

Introduction

Brief history of MSCs

Nomenclature

Biologic role of MSCs in situ

Cell biology of ex vivo expanded MSCs

Immunobiology

Risks of ex vivo expanded MSCs as cell therapy

Clinical applications

Future considerations

References

CHAPTER 8: Genetic Manipulation of Hematopoietic Stem Cells

Introduction and history

Gene transfer vectors

Gene editing and targeted gene integration

Gene transfer to HSCs

Clinical trials of HSC gene transfer

Genetic diseases

Lysosomal storage disorders

Solid tumors

Infectious disease

Vector-mediated insertional mutagenesis

Summary and future directions

References

SECTION 2B: Immunology

CHAPTER 9: Overview of Hematopoietic Cell Transplantation Immunology

Introduction

Fundamental differences between pathogen and transplantation responses

Fundamental differences between hematopoietic cell transplantation and solid organ transplantation

Transplantation antigens

Movement of cells in the immune system

Innate and adaptive immune responses

Regulation of natural killer-cell responses

Self-tolerance and antigen recognition by T cells

T-cell activation, effector differentiation, and effector functions

T-cell differentiation

Costimulatory molecule and cytokine receptor signaling

Peripheral tolerance and regulation of T-cell responses

T-cell memory

Selection of donors for allogeneic HCT

Outcomes influenced by genetic disparity between the donor and recipient

Development of tolerance

Immune reconstitution

Summary and conclusions

References

CHAPTER 10: Histocompatibility

Introduction

HLA genes: structure and function

The history of HLA

Nomenclature

Hallmarks of the MHC: linkage disequilibrium (LD) and haplotypes

Histocompatibility testing of donors for allogeneic transplantation

Conclusions

References

CHAPTER 11: Natural Killer Cells and Allogeneic Hematopoietic Cell Transplantation

Introduction

NK-cell subpopulations: CD56bright and CD56dim NK cells

NK cell Cytotoxicity

MHC-specific NK-cell receptors: KIR and CD94/NKG2A

NK-cell-activating receptors: NKG2D, natural cytotoxicity receptors, and DNAM-1

NK killing of leukemia

NK-cell development from hematopoietic progenitor cells

Innate lymphoid cells (ILCs)

Development of NK-cell self-tolerance

NK-cell reconstitution after allo-HCT

NK–DC interactions

NK cells, viral infections, and NK memory

Clinical studies

Adoptive NK-cell transfer for refractory leukemia and cancer

Conclusion

References

CHAPTER 12: Mechanisms of Tolerance

Introduction

General mechanisms of alloreactive T-cell immune tolerance

Induction of host immune tolerance to organ allografts

Summary and future directions

Acknowledgments

References

CHAPTER 13: The Pathophysiology of Graft-versus-Host Disease

Acute GVHD pathophysiology: a three-step model

Step 1: effects of conditioning

Step 2: Donor T-cell activation and cytokine secretion

Step 3: cellular and inflammatory effectors

GVHD prevention: from animal models to clinical practice

Step 1: reduced-intensity conditioning regimens

Step 2: modulation of donor T cells

Step 3: blockade of inflammatory stimulation and effectors

Chronic GVHD

Conclusion

References

CHAPTER 14: Immune Regulation in Hematopoietic Cell Transplantation

Introduction

Regulatory cell populations

Conclusion

References

CHAPTER 15: Immune Reconstitution Following Hematopoietic Cell Transplantation

Introduction

Steady-state lymphopoiesis

What are the causes of post-transplant immune deficiencies?

Consequences of prolonged immune depletion

Endogenous immune reconstitution after HCT

Functional analysis of T-cell reconstitution (monitoring)

Therapeutic strategies to improve immune reconstitution

Conclusion

References

CHAPTER 16: Biology of the Human Graft-versus-Tumor Response and How to Exploit It

Defining characteristics of the graft-versus-tumor effect in human allogeneic hematopoietic cell transplantation

Identifying the genetic determinants, effector cells, and target molecules of the GVT effect

Strategies for exploiting the GVT response

Conclusion

References

CHAPTER 17: Dendritic Cells in Hematopoietic Cell Transplantation

Introduction: the dendritic cell network

DC functions

DC homeostasis in the steady state

Response of DCs to conditioning therapy

Homeostasis after transplant: content of the graft

Acute GVHD

Chronic GVHD

GVL effect

DCs as potential therapeutic targets in transplant settings

Conclusion

References

CHAPTER 18: The Experimental Basis for Hematopoietic Cell Transplantation for Autoimmune Diseases

Introduction

The immune response

Autoimmune pathology

Animal models of ADs

HCT and the treatment of ADs

Autologous HCT

Allogeneic HCT

Conclusion

References

SECTION 2C: Technical Aspects

CHAPTER 19: Pharmacologic Basis for High-dose Chemotherapy

Introduction

Pharmacology of drugs used in high-dose chemotherapy

Conclusion

References

CHAPTER 20: High-dose Preparatory Regimens

Introduction

Evaluation of new treatment regimens

Marrow ablative agents – maximum tolerated dose (MTD) when administered with HCT (Table 20.1)

High-dose chemotherapy regimens (Tables 20.5–20.9)

Non-marrow ablative agents and agents for which MTD with stem-cell support is not known

High-dose regimens with total body irradiation

High-dose chemotherapy versus high-dose chemoradiotherapy (Table 20.10)

Marrow ablation using targeted radioisotopes

Conclusion

References

CHAPTER 21: Reduced-intensity Allogeneic Transplantation Regimens

Introduction

Preclinical canine studies

Clinical results

Conclusion

References

CHAPTER 22: Radiotherapeutic Principles of Hematopoietic Cell Transplantation

Introduction

Radiobiology principles

Radiation physics and physical considerations

High-dose TBI-containing regimens: clinical results

High-dose TBI-containing regimens: normal tissue effects

Acute toxicities associated with high dose TBI-containing regimens

High-dose TBI versus non-TBI regimens

TBI and reduced-intensity conditioning (RIC) regimens

Total lymphoid irradiation (TLI)

Involved field radiotherapy

Targeted total body irradiation and future directions

Key points

References

CHAPTER 23: Radioimmunotherapy and Hematopoietic Cell Transplantation

Background

Components of RIT

Leukemia

Toxicity

Future directions

Conclusion

References

CHAPTER 24: Documentation of Engraftment and Characterization of Chimerism After Hematopoietic Cell Transplantation

Genetic markers in hematopoietic cell transplantation

Methods for evaluating chimerism

Molecular cytogenetics

VNTR and STR polymorphisms

DNA amplification of other loci for assessment of chimerism

Clinical application of chimerism tests

Other applications for genetic marker studies

Biologic insights from genetic marker studies

Conclusion

References

CHAPTER 25: The Detection and Significance of Minimal Residual Disease

Introduction

Methods of MRD detection

The clinical significance of MRD

Conclusion – the future of MRD

References

CHAPTER 26: Pathology of Hematopoietic Cell Transplantation

Introduction

Pre-transplant evaluation

Post-transplant hematopoietic evaluations

Role of the microvasculature in transplant complications

Graft-versus-host disease

Skin

Oral GVHD

Gastrointestinal GVHD

Esophageal GVHD

Autologous GVHD

Hepatic GVHD

Pulmonary complications

Pulmonary GVHD

Other sites involved in chronic GVHD

Infection

Additional comments

References

CHAPTER 27: Biostatistical Methods in Hematopoietic Cell Transplantation

Introduction

Statistical methods in HCT research

Clinical trial design in HCT research

Observational study designs

References

CHAPTER 28: Outcomes Research in Hematopoietic Cell Transplantation

Introduction

Definition

History

Specific questions for the field of HCT

Conclusion

References

SECTION 3: Patient-oriented Issues in Hematopoietic Cell Transplantation

CHAPTER 29: The Evaluation and Counseling of Candidates for Hematopoietic Cell Transplantation

Introduction

Written information for patients

The patient’s first visit to the transplant center

Advice on counseling new patients

The problem of permanent infertility

The choice of transplant procedure

Which outcomes data should one quote?

What does the patient hear and remember?

The second counseling meeting

When to advise against HCT

How to counsel patients seeking multiple opinions

The new foreign patient

The issue of clinical trials

Conditions affecting treatment outcomes

Psychosocial assessment

Special considerations for pediatric transplant candidates

Some final considerations

References

CHAPTER 30: Nursing Role in Hematopoietic Cell Transplantation

Introduction

Prework-up/prior to arrival at the transplant center (Table 30.1)

Work-up (Table 30.2)

Preconditioning (Table 30.3)

Donor preparation (Table 30.4)

Mobilization and collection (autologous patients and allogeneic donors) (Table 30.5)

Conditioning (Table 30.6)

Bone marrow harvest (Table 30.8)

Transplant phase (Table 30.9)

Pre-engraftment (Table 30.10)

Early post-engraftment (Table 30.11)

Intensive care management of the transplant patient

Relapse post-transplant

Discharge (Table 30.12)

Long-term recovery (Table 30.14)

Nursing practice issues in hematopoietic stem-cell transplant

Conclusion

Acknowledgments

References

CHAPTER 31: Ethical Issues in Hematopoietic Cell Transplantation

Introduction

Who is eligible for HCT?

Informed consent for patients undergoing HCT

Informed consent for donors of hematopoietic cells

Alternative sources of hematopoietic cells

Transplantation for non-malignant diseases

End-of-life issues

Conclusion

References

CHAPTER 32: Psychosocial Issues in Hematopoietic Cell Transplantation

Introduction

Factors influencing psychosocial issues in HCT

Prominent psychosocial stressors in HCT

Stages of HCT and associated psychosocial issues

Psychosocial Issues in HCT: informal caregivers

Conclusion

References

CHAPTER 33: Assessment of Quality of Life in Hematopoietic Cell Transplantation Recipients

Introduction

Definition of health-related QOL

Dimensions of QOL

Phases of HCT and related risk factors for QOL outcomes

Pediatric QOL

Caregivers and parents of transplant recipients

QOL measurement

Clinical utility of QOL data

Conclusion

Acknowledgment

References

CHAPTER 34: Sexuality Following Hematopoietic Cell Transplantation

Introduction

Conceptualizing sexuality

Alterations in sexual health following HCT

Etiology of altered sexual health in HCT recipients

Assessment and interventions for altered sexual health

Areas for future research

Conclusion

References

CHAPTER 35: Hematopoietic Cell Transplantation

Preparing for transplant

Put the risks into perspective

Communication in lay language

Repetition and reinforcement are important

Different learning styles

Discussing pain control is important

Discuss psychologic difficulties

Psychosocial support networks for patients and their families

Quality of life post-transplant

Chronic GVHD

Other resources for patients and survivors

Conclusion

References

SECTION 4: Sources of Hematopoietic Cell for Hematopoietic Cell Transplantation

CHAPTER 36: Hematopoietic Cell Procurement, Processing, and Transplantation

Introduction

Governmental regulation

Role of the FDA

Cord blood cells

State regulation

Stem cell Acts

Voluntary professional accreditation

Other Standards

Future directions

References

CHAPTER 37: Bone Marrow and Peripheral Blood Cell Donors and Donor Registries

Introduction

Products from HC donors

Donors of allogeneic bone marrow and PBPC

Unrelated donors and unrelated donor registries

Donor eligibility and qualification

Donation procedures

Adverse events associated with hematopoietic cell donation

Special considerations

Summary

References

CHAPTER 38: The Role of the Transplant Program in a Nuclear Accident or Terrorism

Introduction

Preparedness and planning for a nuclear detonation

Responding to the consequences of a nuclear incident: concepts, information and resources

Medical management of acute responses to radiation

Radiation Injury Treatment Network (RITN)

Resources for assisting hematologists with clinical management

A role for stem cell transplantation?

Current efforts to develop medical radiation countermeasures

Conclusion

References

CHAPTER 39: Cord Blood Hematopoietic Cell Transplantation

Introduction

Brief historical perspective of the first CB HCTs

CB banking

Clinical results

Immune reconstitution after CB HCT

Future directions for enhancing CB HCT

References

CHAPTER 40: Mobilization of Peripheral Blood Hematopoietic Cells for Autologous HCT

Introduction

Identification and enumeration

Mechanisms of hematopoietic cell mobilization

Evidence for the pivotal role of SDF-1/CXCR4 in HSC mobilization and trafficking

Clinical applications

Collection techniques

Identifying the optimal cell yield

Cytokine and cytokine plus chemokine-induced mobilization

Combination cytokine, pegylated cytokine, and cytokine plus chemotherapy-induced mobilization

Factors affecting yield of PBPC mobilization

Managing poorly mobilizing patients

Tumor contamination

Future directions

Summary

References

CHAPTER 41: Peripheral Blood Hematopoietic Cells for Allogeneic Transplantation

Introduction

The donors

The recipients

Conclusion and future developments

References

CHAPTER 42: Cryopreservation of Hematopoietic Cells

Introduction

Non-frozen storage of HC products

Cryopreservation theory

The physics of cooling and warming of cell products

Cryoprotectant solutions

Cryopreservation technique

Cryoprotectant toxicity

Special considerations

Summary

References

CHAPTER 43: Use of Recombinant Growth Factors after Hematopoietic Cell Transplantation

Introduction

Erythropoietin

Granulocyte colony-stimulating factor

Other hematopoietic growth factors and cytokines

Keratinocyte growth factor

Conclusion

References

CHAPTER 44: Hematopoietic Cell Transplantation from Human Leukocyte Antigen Partially Matched Related Donors

Introduction

Donor selection

Transplantation of T-replete marrow grafts

Transplantation of T-cell-depleted hematopoietic cell grafts

Conclusion

References

CHAPTER 45: Hematopoietic Cell Transplantation from Unrelated Donors

Introduction

Patient factors

Transplant factors

Product factors

Donor factors

New frontiers: the clinical importance non-HLA gene polymorphisms

Conclusion

References

SECTION 5: Hematopoietic Cell Transplantation for Acquired Disease

CHAPTER 46: Hematopoietic Cell Transplantation for Aplastic Anemia

Epidemiology

Clinical description

Etiology

Molecular and clinical biology

Hematopoietic cell transplantation

Conclusion

References

CHAPTER 47: Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria

Introduction

Pathogenesis of PNH

Clinical manifestations

Natural history and prognosis

Diagnosis

Non-transplant treatment of PNH

Transplantation for PNH

Transplants following reduced-intensity conditioning

Use of eculizumab during HCT

Autologous transplantation for PNH

Conclusion

References

CHAPTER 48: Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia

Introduction

The past: allogeneic hematopoietic cell transplantation as curative therapy in CML

Relapse following transplantation

Autologous transplantation

The Present: TKI therapy and the more limited role of transplantation

Who and when do we transplant?

The future of CMLtreatment

References

CHAPTER 49: Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia

Introduction

Classification and epidemiology

Clinical presentation and differential diagnosis

Hematologic features

Chromosomal abnormalities

Molecular pathogenesis

Natural course and prognostic factors

Non-transplant approaches

Hematopoietic cell transplantation

Outlook

References

CHAPTER 50: Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia

Introduction

Epidemiology and etiology

Molecular and cellular biology

Classification

Clinical and laboratory presentation

Non-transplant approach to treatment

Hematopoietic cell transplantation

Conclusion

References

CHAPTER 51: Hematopoietic Cell Transplantation for Childhood Acute Myeloid Leukemia

Introduction

Epidemiology/classification/molecular and cellular biology

Karyotypic alterations

Somatic mutations

The role of HCT in CR1 AML

The role of allogeneic HCT in CR2 + AML

A limited role for autologous HCT in CR2 AML

Outcomes of children undergoing HCT with AML not in remission

Pre-HCT MRD positivity: effect on survival

The role of HCT in acute promyelocytic leukemia

The role of HCT in therapy-related AML

Effect of hematopoietic cell source on outcomes

Preparative regimens for pediatric AML patients

Reduced-intensity conditioning (RIC) regimens in pediatric AML

The graft-versus-leukemia (GVL) effect in pediatric AML

Relapse after HCT

Second HCT

Conclusions – targeted chemotherapeutic, HCT, and cellular approaches to pediatric AML

References

CHAPTER 52: Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Adults

Introduction

Etiology

Signs and symptoms of disease

Clonal origin of leukemic lymphoid cells

Lineage-specific features of leukemic lymphoblasts

Cytogenetic and molecular genetic analyses

Treatment of ALL in adults

Treatment strategy for ALL

Future considerations

References

CHAPTER 53: Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Children

Introduction

Diagnosis and classification of ALL in childhood

Biologic differences between pediatric and adult ALL

Outcome of sibling donor transplantation in children with ALL

Selection of conditioning regimens

Alternative donor HCT for children with ALL

Special pediatric considerations

Role of second transplant procedures for relapse

Conclusion

References

CHAPTER 54: Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Introduction

General considerations for hematopoietic cell transplantation in patients with MDS and MPN

Myelodysplastic syndromes

Myeloproliferative neoplasms

Myelodysplastic/myeloproliferative neoplasms

Autologous HCT

Relapse after HCT

GVHD

Conclusions and perspective

References

CHAPTER 55: Hematopoietic Cell Transplantation for Multiple Myeloma

General aspects of myeloma

Myeloma therapy

Autologous stem-cell transplantation for myeloma

Allogeneic HCT in myeloma

Conclusion

References

Index

End User License Agreement

Volume 2

Title Page

Contributors

Preface to the First Edition

Preface to the Fifth Edition

Tribute

List of Abbreviations

CHAPTER 56: Hematopoietic Cell Transplantation for Hodgkin Disease

Epidemiology and etiology

Molecular and clinical biology

Clinical description

Non-transplant approaches

Hematopoietic cell transplantation

Summary and future directions

References

CHAPTER 57: Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma (B Cell)

Introduction

Diffuse large B-cell lymphoma

Double hit lymphoma

Mantle cell lymphoma

Follicular lymphoma

HCT for transformed lymphoma

Burkitt lymphoma

Lymphoblastic lymphoma

Involved field radiotherapy after HCT

Conclusion

References

CHAPTER 58: Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma (T Cell)

Introduction

Diagnosis and treatment of T-cell NHL

HCT for systemic or peripheral NK/T-cell lymphoma (PTCL)

HCT for cutaneous T-cell lymphoma (CTCL)

Conclusion and future directions

References

CHAPTER 59: Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia

Introduction

Epidemiology

Etiology

Clinical presentation, diagnosis, and staging

Prognostic markers

Response criteria

Minimal residual disease – methods for monitoring depth of treatment response

Initial CLL therapy

Clinical challenges in advanced and high-risk CLL

Historical experience with autologous transplantation

Allogeneic transplantation

Treatment of post-transplant relapse

Novel agents in CLL

Cell therapy

Conclusion

References

CHAPTER 60: Autologous Hematopoietic Cell Transplantation for Systemic Light Chain (AL-) Amyloidosis

Introduction

Epidemiology

Pathogenesis

Diagnosing AL-amyloidosis

Clinical presentations

Prognosis and eligibility for HCT at diagnosis

Therapy

Conclusion

References

CHAPTER 61: Autologous Hematopoietic Cell Transplantation for Breast Cancer and Germ-cell Tumors

Introduction

Hematopoietic cell transplantation for breast cancer

Germ-cell tumors

Special considerations

Conclusion

References

CHAPTER 62: Hematopoietic Cell Transplantation for Renal Cell Carcinoma and Other Solid Tumors

Introduction

Allogeneic transplantation as immunotherapy: the GVT effect

The immune system and solid tumors

Solid tumors as a GVT target

Use of reduced-intensity conditioning in allogeneic transplantation for solid tumors

Clinical results of reduced-intensity allogeneic HCT transplantation in solid tumors

Emerging role of RIC HCT for RCC

Toxicities and limitations of RIC HCT in metastatic RCC

RIC HCT in melanoma

RIC HCT in other solid tumors

Mechanisms underlying GVT effects in solid tumors

Future directions

References

CHAPTER 63: Hematopoietic Cell Transplantation for Neuroblastoma

Introduction

Clinical presentation and staging

Tumor molecular biology

Risk classification and treatment approach

Treatment of high-risk neuroblastoma

Induction therapy

Local control

Autologous hematopoietic cell rescue

Non-randomized comparisons of autologous HCT with chemotherapy

Randomized comparison of autologous HCT with standard-dose chemotherapy

High-dose conditioning regimens

Tandem transplants

Targeted radionuclides as part of high-dose therapy

Allogeneic transplantation

Hematopoietic cell source and purging

Minimal residual disease

Acute and late complications of HCT in neuroblastoma

Conclusion

References

CHAPTER 64: Hematopoietic Cell Transplantation for Other Pediatric Solid Tumors

Introduction

Indications and outcomes

Future directions

Conclusion

References

CHAPTER 65: Hematopoietic Cell Therapy for Human Immunodeficiency Virus Infection

Introduction

The pathogenesis of HIV-1 infection and AIDS

Allogeneic transplantation in HIV/AIDS patients

Autologous stem-cell transplantation in the AIDS patient with lymphoma

Management of the AIDS patient during HSCT

Gene therapy for HIV/AIDS

Conclusion

References

CHAPTER 66: Hematopoietic Cell Transplantation for Autoimmune Diseases

Introduction

Proposed mechanisms for autoimmunity and autoimmune diseases

Preclinical models of autoimmunity and hematopoietic cell transplantation

Outcomes in patients with autoimmune diseases transplanted for another primary disease

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for autoimmune diseases: clinical experience

Allogeneic hematopoietic cell transplantation for autoimmune diseases: clinical experience

Conclusion

References

CHAPTER 67: Hematopoietic Cell Transplantation for Rare Hematologic Malignancies

Introduction

Rare myeloid malignancies

Rare lymphoid malignancies

References

CHAPTER 68: Adoptive T-cell Therapy for Viral Disease in the Setting of Hematopoietic Cell Transplantation

Introduction

Common viral infections post-transplant

Adenovirus

Prerequisites for T-cell therapy

Clinical results using immunotherapy targeting single viruses

Clinical results using immunotherapies targeting multiple viruses

CTLs for HSCT patients with virus-naïve donors

Conclusions and future directions

References

CHAPTER 69: Adoptive T-cell Therapy for Malignancy in the Setting of Hematopoietic Cell Transplantation

Introduction

History and rationale for adoptive T-cell transfer therapy

Principles of T-cell transfer

Strategies for T-cell culture and engineering

Clinical approaches in the setting of HSCT

Combination approaches using vaccines and adoptive T-cell transfer

Synthetic biology with engineered T cells

Clinical trials with CAR T cells

Clinical trials with transgenic TCR-modified T cells

Incorporating CAR and TCR T cells into stem-cell transplant regimens

Strategies to use engineered T cells as a bridge to transplant

Moving to the dark side: adoptive therapy with T regulatory cells

Dose and scheduling issues

Conclusions and future directions

References

CHAPTER 70: Relapse of Hematologic Malignancy After Allogeneic Hematopoietic Transplantation

Mechanism of relapse post-transplant

Conclusions and future directions

References

SECTION 6: Hematopoietic Cell Transplantation for Inherited Disease

CHAPTER 71: Hematopoietic Cell Transplantation for Thalassemia

Introduction

Epidemiology and etiology

Molecular and clinical biology

Clinical features

Non-transplant approaches

Hematopoietic cell transplantation (HCT)

Management of the ex-thalassemic patient after HCT

The role of HCT in the treatment of thalassemia

References

CHAPTER 72: Hematopoietic Cell Transplantation for Sickle Cell Disease

Introduction

Epidemiology and etiology

Molecular and cellular biology

Clinical description

Therapeutic alternatives to HCT

HCT for SCD

Conclusion

References

CHAPTER 73: Hematopoietic Cell Transplantation for Immunodeficiency Diseases

Introduction

Immunophenotypic and genotypic variants of severe combined immunodeficiency (SCID)

Clinical features of SCID

Early detection of SCID: the potential impact of prenatal diagnosis and newborn screening on transplant outcome

HCT for SCID

Long-term complications in patients transplanted for SCID

Transplantation for other combined immunodeficiency syndromes (CID) and life-threatening genetic disorders of lymphocyte development or function

Wiskott–Aldrich syndrome (WAS)

Conclusion

References

CHAPTER 74: Hematopoietic Cell Transplantation for Storage Diseases

Introduction

HCT for storage diseases

Mucopolysacharidoses (MPS) and mucolipidoses (ML)

MPS DISORDERS FOR WHICH HCT CAN BE BENEFICIAL: MPS I, MPS VI, AND MPS VII

MPS DISORDERS FOR WHICH HCT IS NOT BENEFICIAL: MPS II, MPS III, MPS IV

Leukodystrophies and other white matter diseases

Glycoprotein metabolic and miscellaneous disorders

Future directions

References

CHAPTER 75: Hematopoietic Cell Transplantation for Macrophage, Granulocyte and Osteoclast Disorders

Introduction

General considerations for HCT

Macrophage disorders

Granulocyte disorders

Conclusion

References

CHAPTER 76: Hematopoietic Cell Transplantationfor Fanconi Anemia

Introduction

Early history

Clinical features

Diagnosis

The FA pathway and DNA repair

Pathophysiology of marrow failure and leukemogenesis

Somatic mosaicism

Genotype–phenotype correlations

Non-transplant treatment strategies

Hematopoietic cell transplantation

Future directions

Conclusion

References

SECTION 7: Complications of hematopoietic cell transplantation

CHAPTER 77: Mechanisms and Treatment of Graft Failure

Introduction

Overview of trafficking, homing, and engraftment of HSCs

Definitions

Incidence of graft failure

Causes of graft failure

Strategies for risk reduction of graft failure

Monitoring of graft performance

Interventions for graft failure

Conclusion

References

CHAPTER 78: Blood Group Incompatibilities and Hemolytic Complications of Hematopoietic Cell Transplantation

Introduction

Hemolytic complications of ABO incompatibility

Delayed hemolytic reactions

Management of ABO and Rh incompatibility

Treatment of pure red cell aplasia

Hemolysis and thrombotic microangiopathy (TMA) syndrome

Therapy for post-HCT TMA

Conclusion

References

CHAPTER 79: Principles of Transfusion Support Before and After Hematopoietic Cell Transplantation

Introduction

Red blood cell components

Coagulation factor components

Platelet components

Transfusion of platelets

Granulocyte concentrates and granulocyte transfusion

Transfusion strategies in HCT

Prevention of transfusion-transmitted CMV infection

Prevention of transfusion-associated GVHD

Transfusion therapy for HCT donors

Conclusion

Acknowledgment

References

CHAPTER 80: Vascular Access and Complications

Introduction

Indications and patient selection

Catheter selection

Insertion site selection

Insertion technique

Catheter care

Complications

Catheter removal

References

CHAPTER 81: Pharmacologic Prevention of Acute Graft-versus-Host Disease

Historical development

Pathogenesis

Alloreactivity

Predictive factors

Non-specific immunosuppressive drugs

Specific T-cell immunosuppressive drugs

Antibodies

Other agents

Conclusion

References

CHAPTER 82: T-cell Depletion to Prevent Graft-versus-Host Disease

Introduction

Early preclinical models of T-cell depletion

T-cell dose and GVHD

Specificity of TCD

Organ Dysfunction and TCD

Engraftment and TCD

Immune reconstitution and infectious complications after TCD HCT

Disease relapse and TCD

Novel approaches to graft manipulation

Conclusion

References

CHAPTER 83: Manifestations and Treatment of Acute Graft-versus-Host Disease

Background, definition, and incidence of acute graft-versus-host disease

Incidence and staging

Risk factors for acute GVHD

Clinical features of acute GVHD

Diagnosis and differential diagnosis

Prediction and prognostication of acute GVHD

Therapy of acute GVHD

Special scenarios

Conclusion

References

CHAPTER 84: Chronic Graft-versus-Host Disease – Clinical Manifestations and Therapy

Introduction

Risk factors for onset of chronic GVHD

Risk factors associated with increased non-relapse mortality and inferior survival

Risk factors associated with duration of therapy

Pathogenesis in humans

Diagnosis of cGVHD

Organ severity staging of cGVHD

Global severity staging of cGVHD

Histopathology and diagnosis of cGVHD

Management of cGVHD

Graft-versus-leukemia effect

Future directions

Acknowledgments

References

CHAPTER 85: Bacterial Infections

Introduction

Biology of bacterial pathogens

Antibiotic resistance

Compromised host defenses

Spectrum of bacterial infections

Treatment strategies

Preventive strategies

Adjunctive measures

Conclusion

References

CHAPTER 86: Fungal Infections After Hematopoietic Cell Transplantation

Introduction

Infections caused by Candida species

Infections caused by Aspergillus species

Less common fungi

Other fungal infections

Conclusion

References

CHAPTER 87: Cytomegalovirus Infection

Introduction

Clinical aspects of CMV infection

Prevention of CMV infection after HCT

CMV-associated diseases after HCT

Treatment of CMV-associated diseases

Cellular Immunity to CMV

Future developments relating to CMV infection in HCT

Conclusion

References

CHAPTER 88: Herpes Simplex Virus Infections

Introduction

Virology

Pathogenesis

Immunology

Epidemiology

Clinical manifestations

Diagnosis

Management of HSV infection in HCT

Prophylaxis

Conclusion

References

CHAPTER 89: Varicella Zoster Virus Infections

Introduction

The virus

Epidemiology

Mechanisms of pathogenesis and viral immune evasion

The host response

Clinical manifestations

Laboratory diagnosis

Antiviral therapy for VZV infection

Prophylaxis for VZV infection

Conclusion

References

CHAPTER 90: Epstein–Barr Virus Infection

Introduction

Aspects of EBV biology

Allogeneic HCT and EBV-PTLD risk factors

EBV-PTLD presentation and diagnosis

EBV monitoring

Treatment and prevention

EBV-PTLD

Treatment of other EBV-associated tumors

Conclusion

References

CHAPTER 91: Respiratory Viruses After Hematopoietic Cell Transplantation

Introduction

Respiratory syncytial virus

Human metapneumovirus

Parainfluenza viruses

Influenza viruses

Human rhinoviruses

Human coronaviruses

Human bocavirus

WU and KI polyomaviruses

Measles virus

Conclusions and future perspective

Acknowledgments

References

CHAPTER 92: HHV-6A, HHV-6B, HHV-7, and HHV-8 After Hematopoietic Cell Transplantation

Introduction

Human herpesviruses 6A and 6B

Human herpesvirus-7

Human herpesvirus-8

Conclusion and future development

References

CHAPTER 93: Human Adenovirus, Polyomavirus, and Parvovirus Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction

Human adenovirus

Virologic aspects

Human polyomaviruses

Human parvovirus

References

CHAPTER 94: Gastrointestinal and Hepatic Complications

Introduction

Evaluation of intestinal and liver problems before transplant

Problems from transplant through the first year

Problems in long-term transplant survivors

References

CHAPTER 95: Lung Injury Following Hematopoietic Cell Transplantation

Introduction

Diagnostic considerations and role of bronchoalveolar lavage

Infectious lung injury

Non-infectious, acute lung injury

Non-infectious, late-onset lung injury: obstructive and restrictive lung disease

Conclusion

References

CHAPTER 96: Kidney and Bladder Complications of Hematopoietic Cell Transplantation

Introduction

Acute kidney injury

Chronic kidney disease

Bladder complications after HCT

Conclusion

Acknowledgment

References

CHAPTER 97: Endocrine Complications Following Hematopoietic Cell Transplantation

Introduction

Hypothalamic–pituitary dysfunction

Growth disorders

Dysfunctional bone metabolism and osteoporosis

Thyroid dysfunction

Metabolic and electrolyte abnormalities

Adrenal dysfunction

Gonadal dysfunction

Sexual dysfunction

Conclusion

References

CHAPTER 98: Common Potential Drug Interactions Following Hematopoietic Cell Transplantation

Introduction

P-glycoprotein (P-gp) system

Organic Anion-Transporting Polypeptide (OATP) system

Cytochrome P450 (CYP450) isoenzyme system

Uridine 5′-diphosphate glucuronosyltransferase (UGT) enzyme system

Azole antifungals

Immunosuppressants

Chemotherapy

Statins

Therapeutic drug monitoring (TDM)

Conclusion

References

CHAPTER 99: Nutrition Support of the Hematopoietic Cell Transplant Recipient

Introduction

Nutrition assessment

Nutrient and fluid requirements

Nutrition support

Special management problems

Long-term complications and management

Conclusion

References

CHAPTER 100: Pain Management

Introduction

Anatomy and physiology of pain

The clinical phenomenon of pain

Assessment of pain and treatment efficacy

Non-pharmacologic techniques in pain management

Non-opioid pharmacologic management of pain

Opioids in the management of pain

Clinical pain management in the HCT patient

Analgesia/sedation for painful and unpleasant procedures

Invasive analgesic techniques in the HCT patient

Analgesia and sedation in dying patients

Conclusion

References

CHAPTER 101: Oral Complications of Hematopoietic Cell Transplantation

Introduction

Correlations with the phases of transplantation

Pre-transplantation oral evaluation and stabilization

Post-HCT oral complications

Conclusion

References

CHAPTER 102: Growth and Development After Hematopoietic Cell Transplantation

Introduction

Thyroid function

Growth

Puberty

Conclusion

References

CHAPTER 103: Delayed Non-malignant Complications After Hematopoietic Cell Transplantation

Introduction

Cardiovascular risk factors and cardiac disease

Delayed pulmonary complications

Endocrine complications

Fertility

Osteonecrosis

Chronic kidney disease

Visual impairments

Chronic disease burden after hematopoietic cell transplantation

Late mortality

Health behaviors of long-term survivors of hematopoietic cell transplantation

Quality of life after hematopoietic cell transplantation

Long-term follow-up

References

CHAPTER 104: Subsequent Malignant Neoplasms After Hematopoietic Cell Transplantation

Introduction

MDS and AML after autologous HCT

Lymphomas

Solid tumors

Conclusion

References

CHAPTER 105: Neurologic Complications of Hematopoietic Cell Transplantation

Introduction

Infectious complications

Cerebrovascular complications

Metabolic complications

Neurologic manifestations of recurrent disease

Immune-mediated complications of the central nervous system: a real entity?

Immune-mediated abnormalities of the peripheral nervous system

Complications from the calcineurin inhibitors cyclosporine and tacrolimus

Complications from other immunosuppressive drugs

Complications from conditioning agents

Complications from supportive care drugs

Pre-transplantation neurologic screening

References

CHAPTER 106: Vaccination of Allogeneic and Autologous Hematopoietic Cell Recipients

Introduction

Scope of the problem

Loss of humoral immunity and vaccination guidelines

Immunogenicity of vaccines after HCT

Conclusion

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Problem areas of allogeneic and autologous hematopoietic cell transplantation. Problems are listed in chronological order as they occur in the course of the respective transplant procedure

Chapter 02

Table 2.1 Diseases in which autologous and/or allogeneic hematopoietic cell transplants may be used

Chapter 03

Table 3.1 Sources of stem cells and their differentiation potential

Chapter 05

Table 5.1 Components of the niche and their role in mobilization

Table 5.2 Mobilization agents and their mechanism

Chapter 07

Table 7.1 Summary of criteria to identify mesenchymal stromal cells

Chapter 08

Table 8.1 Recent hematopoietic stem cell (HSC) clinical gene therapy studies

Chapter 09

Table 9.1 Immune responses to transplantation versus pathogens

Table 9.2 Receptors and ligands involved in costimulation

Chapter 10

Table 10.1 Definition of commonly used terms in histocompatibility

Table 10.2 The International Histocompatibility Workshops

Table 10.3 Models for natural killer immunoglobulin-like receptor (KIR) ligands in unrelated donor hematopoietic cell transplantation

Table 10.4 Vector of HLA mismatch

Chapter 13

Table 13.1 Examples of approaches to prevent or treat GVHD

Table 13.2 National Institutes of Health consensus conference categories of graft-versus-host disease

Chapter 14

Table 14.1 Immune regulatory populations in allogeneic stem-cell transplantation

Chapter 15

Table 15.1 Tests for analysis of immune reconstitution

Chapter 18

Table 18.1 Associations of HLA type with susceptibility to autoimmune disease

Table 18.2 Animal models of autoimmune disease

Table 18.3 Selected non-MHC major associations with autoimmune diseases

Chapter 19

Table 19.1 Conditioning regimen drugs given to HSCT recipients registered with the CIBMTR between 2009 and 2011

Chapter 20

Table 20.1 Maximum tolerated dose (MTD) of single-agent therapies used with hematopoietic cell transplantation

Table 20.2 Maximum tolerated doses of total body irradiation (TBI) given with cyclophosphamide 120 mg/kg

Table 20.3 Randomized trials of total body irradiation regimens given with cyclophosphamide 120 mg/kg

Table 20.4 Chemotherapeutic agents given with total body irradiation (TBI) and with or without cyclophosphamide

Table 20.5 Busulfan/treosulfan-based regimens

Table 20.6 Nitrosourea-based high-dose chemotherapy regimens

Table 20.7 Melphalan-based high-dose regimens

Table 20.8 ThioTEPA-based high-dose regimens

Table 20.9 Etoposide-based high-dose regimens

Table 20.10 Randomized trials of BU/CY versus TBI ± VP16 ± CY

Chapter 21

Table 21.1 Nonmyeloablative conditioning regimens for patients with hematologic malignancies

Table 21.2 Relapse rates per patient-year among 1,092 patients

Chapter 22

Table 22.1 Select randomized trials comparing TBI- with non-TBI-containing high-dose HCT conditioning regimens

Table 22.2 Select non-randomized studies comparing TBI- with non-TBI-containing high-dose HCT conditioning regimens

Table 22.3 Median dose to normal organs with TMI using tomotherapy compared with standard TBI to deliver 12 Gy

Table 22.4 Summary of toxicities observed on TMI trials at City of Hope Cancer Center

Chapter 23

Table 23.1 Factors that influence biodistribution of radiolabeled antibodies.

Table 23.2 Radionuclides for radioimmunotherapy

Chapter 24

Table 24.1 Clinical applications of chimerism tests in hematopoietic cell transplantation

Table 24.2 Testing of isolated cell populations by single- or dual-color fluorescence in situ hybridization (FISH) to detect recurrent leukemia

Chapter 25

Table 25.1 Common assays used for detection of minimal residual disease (MRD)

Table 25.2 Minimal residual disease (MRD) studies in childhood acute lymphoblastic leukemia

Table 25.3 Studies examining the impact of minimal residual disease (MRD) on outcome of adult acute leukemia (ALL and AML) in the non-transplant setting

Table 25.4 Studies examining the impact of pre- or post-hematopoietic cell transplantation minimal residual disease (MRD) levels in ALL and AML on subsequent relapse and transplant outcome

Chapter 26

Table 26.1 Histological Criteria for GVHD by Organ System

Chapter 27

Table 27.1 Results from fitting a stepwise Cox regression model for overall mortality among 1007 MDS patients

Table 27.2 Hierarchy of strength of evidence concerning efficacy of treatment

Chapter 28

Table 28.1 Examples of cost-effectiveness and cost–utility studies in hematopoietic cell transplantation (HCT) and medicine

Table 28.2 Levels of evidence and grades of recommendation

Chapter 29

Table 29.1 Issues and topics that should be addressed during counseling meetings with transplant candidates and their families

Table 29.2 Discrepancies between patient and physician estimates for the success of HCT [8]

Table 29.3 Karnofsky performance status scale [32]

Table 29.4 HCT-specific comorbidity index score [87]

Table 29.5 General eligibility criteria for adult candidates for allogeneic or autologous HCT

Table 29.6 Goals of the psychosocial assessment of adult HCT candidates

Table 29.7 The Lansky play-performance scale [130] (for use with persons aged 1–16 years)

Chapter 30

Table 30.1 Prework-up/prior to patient’s arrival at transplant center

Table 30.2 Work-up

Table 30.3 Preconditioning

Table 30.4 Donor work-up

Table 30.5 Mobilization and collection (autologous patients and allogeneic donors)

Table 30.6 Conditioning

Table 30.7 Quick reference for symptoms

Table 30.8 Bone marrow harvest

Table 30.9 Transplant

Table 30.10 Pre-engraftment

Table 30.11 Early post-engraftment

Table 30.12 Discharge from transplant program

Table 30.13 Common questions asked by hematopoietic stem-cell transplantation (HSCT) and long-term follow-up (LTFU) patients utilized at the Fred Hutchinson Cancer Research Center

Table 30.14 Long-term recovery

Table 30.15 Nursing role descriptions in hematopoietic stem cell transplantation

Chapter 32

Table 32.1 Themes, tasks, and psychosocial issues associated with four stages of HCT

Chapter 33

Table 33.1 Selected QOL measures used in HCT

Table 33.2 Subscales of the most widely used adult global health-related QOL measures, reliability and validity established in HCT populations

Chapter 34

Table 34.1 Investigations of altered sexual health following HCT

Chapter 36

Table 36.1 Foundation for the Accreditation of Cellular Therapy (FACT) Inspector Qualifications

Table 36.2 Foundation for the Accreditation of Cellular Therapy (FACT) potential accreditation outcomes

Chapter 37

Table 37.1 Deaths occurring in association with hematopoietic cell donation

Chapter 38

Table 38.1 The spectrum of potential events involving radioactive material. Numbers of deaths are rough estimates

Table 38.2 Strategies for scarce resource situations

Table 38.3 Websites containing additional information on approaches to medical triage, assessment and management after radiation exposure (websites accessed January 2015)

Chapter 39

Table 39.1 Diagnosis of children transplanted with HLA identical sibling CB

Table 39.2 Advantages and limitations of unrelated donor BM, CB, and haploidentical cells from a relative, and main criteria to be considered for choosing an alternative donor for patients without an HLA-identical sibling

Table 39.3 Diagnosis and numbers of children transplanted with unrelated CB cells and reported to Eurocord registry

Table 39.4 Recommendations for unrelated cord blood unit selection and transplantation

Chapter 40

Table 40.1 Comparison of mobilization with granulocyte colony-stimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF)

Table 40.2 Comparisons of cytokine doses and combinations for mobilization

Table 40.3 Comparison of cytokine alone versus cytokine + chemotherapy

Table 40.4 Guidelines for the hard to mobilize patient [refs]

Table 40.5 Preclinical mobilization studies

Table 40.6 Recommendations for standard mobilization regimens

Chapter 41

Table 41.1 Characteristics of CD34+ hematopoietic cells (HCs) from bone marrow (BM) or mobilized peripheral blood (PB)

Table 41.2 Subject incidence of adverse events occurring in >5% of donors. Date from the EBMT study comparing bone marrow transplantation (BMT) with peripheral blood progenitor cell transplantation (PBPCT) [28]

Table 41.3 Acute graft-versus-host disease (GVHD) grades II–IV

Table 41.4 Chronic graft-versus host disease (GVHD)

Chapter 42

Table 42.1 Hematopoietic cell cryopreservation: basic technical considerations

Table 42.2 Recoveries of nucleated cells and hematopoietic cells after cryopreservation with ethylene glycol or dimethylsulfoxide (DMSO)

Table 42.3 Effect of product volume on cooling rate after immersion into a –70 °C freezer: rates of cooling before and after the transition phase, and the duration of the transition phase for samples of the stated volumes immersed into a 70 °C refrigerator

Table 42.4 Engraftment kinetics of patients receiving peripheral blood hematopoietic cells frozen in dimethlysulfoxide (DMSO) or DMSO and hydroxyethyl starch (HES)

Table 42.5 Protective effect of various additives for murine marrow cryopreservation: viability of bone marrow cells cryopreserved with various additives as shown by vital dye stains and the ability of these cells to rescue an animal from irradiation

Table 42.6 Effect of cryoprotectant on optimal cooling rate for murine colony-forming units – spleen (CFU-S)

Table 42.7 Engraftment and outcome for transplantation of cryopreserved marrow from allogeneic donors

Chapter 43

Table 43.1 Growth factors available for clinical use

Table 43.2 Randomized placebo controlled trials of G-CSF following HCT

Table 43.3 Randomized trials of pegfilgrastim versus filgrastim following HCT

Chapter 44

Table 44.1 Mismatching according to vector of genetic disparity for human leukocyte antigen (HLA)-A, -B, and -DR

Table 44.2 Effect of HLA incompatibility on marrow graft failure

Table 44.3 Human leukocyte antigen (HLA) class I specificity of the main inhibitory killer immunoglobulin-like receptors (KIRs) expressed by human natural killer (NK) cells

Table 44.4 Human leukocyte antigen (HLA)-C group 1, HLA-C group 2 and HLA-Bw4 group alleles

Table 44.5 Donor–recipient human leukocyte antigen (HLA) class I combinations associated with natural killer (NK) cell alloreactivity in the graft-versus-host direction

Chapter 45

Table 45.1 Role of HLA in unrelated donor hematopoietic cell transplantation

Table 45.2 The role of KIR in unrelated donor hematopoietic cell transplantation

Table 45.3 Summary of studies of cytokine and immune response gene polymorphisms in unrelated donor HCT

Chapter 46

Table 46.1 Selected recent reports of HLA-identical HCT for SAA

Table 46.2 Selected recent reports of HCT from unrelated donors

Chapter 47

Table 47.1 Clinical and laboratory characteristics of paroxysmal nocturnal hemoglobinuria (PNH), AA, and myelodysplasia

Table 47.2 Published reports of transplantation for paroxysmal nocturnal hemoglobinuria (PNH)

Table 47.3 Patients in the Seattle transplant program

Table 47.4 Summary of patients in the Seattle transplant program (n = 28): donor type, conditioning regimen, and survival

Table 47.5 Bone marrow/stem cell transplantation for patients with PNH

Chapter 48

Table 48.1 Definition of accelerated phase chronic myeloid leukemia

Table 48.2 12-month responses (%) in ENESTnd [84], DASISION [82], and US Intergroup [83] trials

Table 48.3 Options for specific BCR-ABL tyrosine kinase domain mutations

Chapter 49

Table 49.1 Diagnostic criteria of JMML

Chapter 50

Table 50.1 World Health Organization classification of acute leukemia with corresponding FAB classification subtypes (2008)

Table 50.2 Cytogenetic classification of AML

Table 50.3 ELN risk stratification for adult AML

Chapter 51

Table 51.1 Comparison of outcomes from studies of autologous transplantation versus chemotherapy in CR1

Table 51.2 Comparison of outcomes from studies of allogeneic transplantation versus chemotherapy in CR1

Table 51.3 Comparison of outcomes from studies of allogeneic HSCT for AML in CR2

Table 51.4 Comparison of outcomes from studies of autologous HSCT for AML in CR2

Chapter 52

Table 52.1 Characteristics of immunologic subtypes of acute lymphoblastic leukemia (ALL)

Table 52.2 Chemotherapy regimens for adult ALL

Table 52.3 Clinical and laboratory risk factors for adult ALL

Table 52.4 Randomized trials in adult ALL comparing allogeneic transplant to non-transplant therapies

Table 52.5 Relapse after transplantation for ALL in CR1 [47]

Table 52.6 Reduced-intensity transplant outcomes for ALL

Chapter 53

Table 53.1 Cellular genotype defines major forms of childhood acute lymphoblastic leukemia

Table 53.2 Indications for transplantation for childhood acute lymphoblastic leukemia

Chapter 54

Table 54.1 IPSS-R prognostic scores

Table 54.2 WHO classification and criteria for MDS

Table 54.3 WHO Classification Based Prognostic Scoring System (WPSS) for MDS

Table 54.4 Allogeneic HCT for MDS

Table 54.5 Classification of MDS and MDS/MPN of childhood

Table 54.6 Risk factors in PMF in the DIPSS classification [126]

Table 54.7 M.D. Anderson criteria for CMML risk category

Chapter 55

Table 55.1 New International Staging System for myeloma

Table 55.2 Definitions for response categories

Table 55.3 Randomized trials addressing autologous stem cell transplant issues in myeloma

Table 55.4 Retrospective analysis of salvage autologous SCT outcomes: series with more than 40 patients

Table 55.5 Auto–allo versus tandem autologous SCT: results of biologic assignment trials among standard-risk patients

Chapter 56

Table 56.1 Results of autologous hematopoietic cell transplantation for Hodgkin disease

Table 56.2 Adverse prognostic factors: autologous hematopoietic cell transplantation for Hodgkin disease

Table 56.3 Potential timing of autologous hematopoietic cell transplantation for Hodgkin disease

Table 56.4 Results of Autologous hematopoietic cell transplantation for primary refractory Hodgkin disease

Table 56.5 Results of autologous hematopoietic cell transplantation for Hodgkin disease after first relapse

Table 56.6 Results of autologous hematopoietic cell transplantation for Hodgkin disease in first remission

Table 56.7 Results of allogeneic hematopoietic cell transplantation for Hodgkin disease

Table 56.8 Commonly used high-dose therapy regimens for Hodgkin disease

Chapter 57

Table 57.1 Reduced intensity alloHCT for relapsed diffuse large B-cell lymphoma

Table 57.2 Phase II trials containing rituximab and cytarabine with autoHCT for newly diagnosed patients with mantle cell lymphoma

Table 57.3 Prospective phase II trials for reduced intensity alloHCT for relapsed follicular lymphoma

Chapter 58

Table 58.1 PTCL and CTCL frequency and survival

Table 58.2 Recent retrospective PTCL trials for autoHCT

Table 58.3 Prospective PTCL trials for autoHCT

Table 58.4 Allogeneic HCT for PTCL

Table 58.5 Autologous HCT for CTCL

Table 58.6 Retrospective Reports on Allogeneic HCT for CTCL

Chapter 59

Table 59.1 Modified Rai and Binet staging systems for CLL

Table 59.2 CLL prognostic markers

Table 59.3 Selected studies of autologous HCT for patients with CLL

Table 59.4 Selected studies of myeloablative allogeneic HCT for patients with CLL

Table 59.5 Selected studies of reduced intensity conditioning (RIC) allogeneic HCT for patients with CLL

Chapter 60

Table 60.1 Patient characteristics (N = 816) (data pooled from six countries) [21]

Table 60.2 Organ response and progression criteria [21,117]

Chapter 61

Table 61.1 Randomized trials of high-dose chemotherapy in metastatic breast cancer

Table 61.2 Randomized trials of high-dose chemotherapy in high-risk primary breast cancer

Table 61.3 Overall results from major phase II trials of HDC with ASCT for breast cancer and germ-cell tumors

Table 61.4 Risk stratification of newly diagnosed patients (International Germ Cell Consensus Classification)

Table 61.5 Prognostic models for HDC for NSGCT

Table 61.6 EFS and OS rates in patients treated with HDC or SDC (International Prognostic Factors Study Group)

Chapter 62

Table 62.1 Tumor response patterns consistent with a graft-versus-tumor effect after reduced-intensity conditioning hematopoietic cell transplantation

Table 62.2 Summary of clinical trials of reduced-intensity conditioning hematopoietic cell transplantation in metastatic renal cell carcinoma

Table 62.3 Limitations of reduced-intensity conditioning hematopoietic cell transplantation in solid tumors

Table 62.4 Patient characteristics likely to predict a favorable outcome after reduced-intensity conditioning hematopoietic cell transplantation for solid tumors

Chapter 63

Table 63.1 International Neuroblastoma Risk Group staging system

Table 63.2 Current Children’s Oncology Group neuroblastoma risk classification

Table 63.3 EFS for high-risk neuroblastoma in first remission using myeloablative therapy and autologous HCT for studies of >20 patients

Chapter 64

Table 64.1 Clinical group definitions for rhabdomyosarcoma patients

Chapter 65

Table 65.1 Outcome of autologous HSCT in high-risk AIDS lymphoma

Table 65.2 Recommendations for cART use during conditioning regimen

Table 65.3 Guidance for dosing of tacrolimus and sirolimus during cART

Table 65.4 Anti-HIV gene therapeutics in clinical trials

Table 65.5 Anti-HIV gene therapeutics in pre-clinical animal studies

Chapter 66

Table 66.1 Single gene defects associated with autoimmunity

Table 66.2 Outcomes in patients with autoimmune diseases transplanted with an allogeneic hematopoietic cell graft for another primary disease

Table 66.3 Clinical trials of HDIT and autologous HCT for multiple sclerosis

Table 66.4 Clinical trials of HDIT and autologous HCT for systemic sclerosis

Chapter 67

Table 67.1 Rare hematologic malignancies for which HCT has been performed

Chapter 68

Table 68.1 Clinical trials using transplant donor-derived single virus-specific CTLs for prophylaxis or treatment of viral infections

Table 68.2 Clinical trials using transplant donor-derived multi virus-specific CTLs for prophylaxis or treatment of viral infections

Table 68.3 Clinical trials using third party virus-specific CTLs

Chapter 69

Table 69.1 Strategies to augment efficacy of adoptive T-cell therapy

Table 69.2 Approaches for engineering lymphocytes

Table 69.3 Potential antigenic targets for CTL therapy

Chapter 70

Table 70.1 Risk factors for relapse after allogeneic transplantation for AML/MDS

Chapter 71

Table 71.1 Pesaro experience of BMT for thalassemia from HLA-matched related donors between May 1985 and December 2003

Table 71.2 Current treatment protocols

Table 71.3 Transplants for thalassemia. Reports from centers other than Pesaro

Chapter 72

Table 72.1 Birth prevalence of β-globin gene variants in a California newborn population, by ethnicity, 1990–1996

Table 72.2 Indications of hematopoietic cell transplantation for sickle cell disease

Table 72.3 Hematopoietic cell transplantation (HCT) for sickle cell disease: published reports

Table 72.4 Neurologic outcomes among surviving patients (n = 55)

Chapter 73

Table 73.1 Genetic mutations and phenotypic characteristics of defined variants of severe combined immunodeficiencies

Table 73.2 Combined immune deficiencies repeatedly corrected by transplantation

Chapter 74

Table 74.1 The mucopolysaccharidoses and mucolipidoses: mode of inheritance, enzyme/protein deficiency, incidence and carrier frequencies, treatment options, and comments

Table 74.2 The leukodystrophies: mode of inheritance, enzyme/protein deficiency, incidence and carrier frequencies, treatment options, and comments [147]

Table 74.3 The glycoprotein disorders and miscellaneous lysosomal storage diseases and inborn errors of metabolism: mode of inheritance, enzyme/protein deficiency, incidence and carrier frequencies, treatment options, and comments [147]

Table 74.4 Guidelines for the pre-hematopoietic cell transplantation (HCT) evaluation (section A) and post-HCT (section B) follow-up of patients with mucopolysaccharide, mucolipidosis, and glycoprotein metabolic disorders

Table 74.5 Guidelines for the pre-hematopoietic cell transplantation (HCT) evaluation (section A) and post-HCT (section B) follow-up of patients with leukodystrophies

Table 74.6 Consensus statement prepared by facilitator Ms Jean Mossman on the orthopedic management of mucopolysaccharidosis (MPS) patients who have had a hematopoietic cell transplant (HCT). Consensus position statements arising from conference held October 3–4, 2003 in Manchester, UK

Table 74.7 Neurologic deficit (e.g., impairments of vision, hearing, speech, gait, fine motor skills, and/or activities of daily living) score before and after hematopoietic cell transplantation (HCT) in 94 patients with cerebral X-adrenoleukodystrophy

Table 74.8 X-linked adrenoleukodystrophy (ALD) Disability Rating Scale (ALD-DRS)

Table 74.9 Neurologic deficits (e.g., impairments of vision, hearing, speech, gait, fine motor skills, and/or activities of daily living), neuropsychologic function, magnetic resonance imaging (MRI) severity, and adrenoleukodystrophy (ALD) Disability Rating Scale (ALD-DRS) levels after hematopoietic cell transplantation in patients with cerebral X-linked ALD according to baseline performance intelligence quotient (PIQ)

Table 74.10 X-adrenoleukodystrophy Disability Rating Scale (ALD-DRS) levels before and after hematopoietic cell transplantation (HCT) in 94 patients with cerebral X-ALD

Table 74.11 Comparison of neuropsychologic functional outcomes according to magnetic resonance imaging pattern of demyelination following hematopoietic cell transplantation (HCT) for cerebral X-linked adrenoleukodystrophy

Chapter 75

Table 75.1 Hematopoietic cell transplantation for macrophage and granulocyte disorders

Table 75.2 Revised diagnostic guidelines for HLH

Table 75.3 Classification of osteopetrosis (OP)

Chapter 76

Table 76.1 List of congenital malformations in Fanconi anemia (FA)

Table 76.2 The Fanconi anemia genes: description and frequency in the IFAR database

Table 76.3 HLA-identical sibling donor HCT: clinical results with radiation-based regimens

Table 76.4 HLA-identical related donor HCT: clinical results with chemotherapy only-based regimens

Table 76.5 Alternative donor HCT: clinical results since 2000

Table 76.6 Observed cancers (O), ratio of observed to expected cancers (O/E), and 95% confidence intervals (95% CI) among North American respondents with Fanconi anemia

Chapter 77

Table 77.1 Definition of graft failure and poor graft function

Table 77.2 Risk factors for graft failure

Table 77.3 Treatment strategies for graft failure

Table 77.4 Second transplants for graft failure

Table 77.5 Considerations for a second allogeneic HCT for graft failure

Chapter 78

Table 78.1 Immunohematologic problems of ABO-incompatible hematopoietic cell transplantation (HCT)

Table 78.2 Management of blood support for ABO-incompatible transplant recipients

Table 78.3 BMT CTN Toxicity Committee consensus criteria [74] and EBMT IWG criteria [75] for TMA

Table 78.4 NCI common toxicity criteria for BMT-associated TMA

Chapter 79

Table 79.1 Adverse effects of leukocytes in blood components

Table 79.2 Clinical situations in which leukodepleted red cells are recommended

Table 79.3 Strategies to reduce transfusion-transmitted disease

Table 79.4 Laboratory testing for transfusion-transmitted diseases

Table 79.5 Estimated risk of transfusion-transmitted infections in the United States

Chapter 80

Table 80.1 Patient and treatment factors that affect catheter selection

Table 80.2 Differences between devices for central venous access

Chapter 81

Table 81.1 Randomized trials of single-agent and combination immunomodulation for prevention of acute GVHD

Table 81.2 Outline of some regimens used for graft-vs.-host disease (GVHD) prophylaxis

Table 81.3 Suggested dose adjustments for methotrexate (MTX)

Table 81.4 Cyclosporine (CSP) drug interactions

Table 81.5 Immunosuppressive drugs, targets, and mechanisms of action discussed in this chapter

Chapter 82

Table 82.1 Methods of T-cell depletion

Table 82.2 Impact of TCD on transplant outcome

Chapter 83

Table 83.1 Modified Glucksberg grading of acute GVHD [4]

Table 83.2 IBMTR grading of acute GVHD [6]

Chapter 84

Table 84.1 Classification of manifestations for the clinical diagnosis of cGVHD

Table 84.2 Distinguishing bronchiolitis obliterans (BO) from cryptogenic organizing pneumonia (COP)

Table 84.3 NIH cGVHD 0–3 scale for scoring severity in each organ

Table 84.4 Indications for systemic therapy according to severity and high-risk features of cGVHD

Table 84.5 Standard 9 months glucocorticoid therapy for cGVHD.

Table 84.6 Considerations for use of the most published agents in cGVHD as second-line therapy or beyond

Table 84.7 Summary of ancillary therapy and supportive care interventions

Chapter 85

Table 85.1 Bacterial virulence factors

Table 85.2 Targets for various antibiotics

Table 85.3 Mechanisms of antibiotic resistance

Table 85.4 Host defenses compromised by hematopoietic cell transplantation (HCT) that make patients vulnerable to bacterial infections

Table 85.5 Bacterial and fungal infectious syndromes encountered early after hematopoietic cell transplantation (HCT), during the pre-engraftment phase (early recovery or phase I)

Table 85.6 Relative frequency of bacterial infections encountered after engraftment (mid- and late recovery, or phases II and III)

Table 85.7 Causes of fevers of obscure origin after engraftment during mid- and late recovery (phases II and III)

Table 85.8 Scoring index for identification of low-risk febrile neutropenic patients at time of presentation with fever

Chapter 86

Table 86.1 Systemic administered antifungal agents

Table 86.2 Host and therapeutic risks for invasive aspergillosis (IA) after allogeneic HCT

Chapter 87

Table 87.1 CMV infection in blood

Table 87.2 Incidence of CMV infection in HCT at City of Hope

Table 87.3 Use of Anti-Cytomegalovirus Antiviral Agents

Chapter 88

Table 88.1 Antiviral prophylaxis and treatment for HSV infection

Chapter 89

Table 89.1 Incidence of VZV infections following HCT, from selected studies

Table 89.2 Risk of recurrent VZV infection after HCT in relation to HLA matching of recipient and donor and the occurrence of GVHD in the recipient

Table 89.3 Distribution of dermatomal involvement with herpes zoster in HCT recipients and healthy individuals with recurrent VZV infections

Table 89.4 Selected studies on antiviral prophylaxis for prevention of VZV infection after HCT

Chapter 90

Table 90.1 Patterns of EBV latent gene expression

Table 90.2 Treatment options for EBV-PTLD

Chapter 91

Table 91.1 Characterization of respiratory virus infections among hematopoietic cell transplantation

Table 91.2 Overview of antiviral agents and antibody preparations against respiratory viral infections after HCT

Chapter 92

Table 92.1 Comparison of findings after HCT in various forms of HHV-6 infection

Table 92.2 Other symptoms and diseases that have been suggested to be associated with HHV-6 infection

Chapter 93

Table 93.1 Working definitions of infection, replication, and disease caused by human adenovirus, polyomavirus, and parvovirus in HCT patients

Table 93.2 Diagnosis of virus-associated hemorrhagic cystitis

Table 93.3 Treatment options for probable and proven disease by human adenovirus, polyomavirus, and parvovirus B19 in HCT patients

Table 93.4 Human polyomavirus and disease

Chapter 94

Table 94.1 Factors that increase the risk of severe sinusoidal liver injury resulting from the conditioning regimen

Table 94.2 Difficult-to-diagnose disorders that can mimic or complicate gastrointestinal acute GVHD

Chapter 95

Table 95.1 Common infectious pathogens of diffuse interstitial pneumonia

Table 95.2 Definition of idiopathic pneumonia syndrome

Table 95.3 The spectrum of non-cardiogenic, pulmonary toxicity defined by IPS

Table 95.4 Risk factors for IPS

Table 95.5 Categorization of the clinical spectrum of lung injury following HCT

Table 95.6 Animal models of IPS

Table 95.7 Treatment options for IPS

Table 95.8 Clinical factors present in OLD versus RLD

Table 95.9 NIH consensus criteria for BOS

Chapter 96

Table 96.1 Definition of terms: A comparison of post-SCT AKI definition and classification according to serum Cr levels in the RIFLE, AKIN, and grading criteria

Table 96.2 Summary of the literature on acute kidney failure (AKF) after hematopoietic cell transplantation (HCT)

Table 96.4 National Kidney Foundation Kidney Disease Outcomes Quality Initiative: chronic kidney disease by stage

Table 96.3 Potential risk factors and mechanisms for AKI in the HCT population

Chapter 97

Table 97.1 Risk factors for growth dysfunction following HCT

Table 97.2 Risk factors for thyroid dysfunction following HCT

Table 97.3 Late consequences in children treated more than 10 years before with two different doses and types of fractionated total body irradiation (FTBI)

Table 97.4 Post-BMT hypothyroidism following cytoreductive therapy regimen without the use of irradiation

Table 97.5 Thyroid function before and after BMT (3 and 14 months)

Table 97.6 Clinical presentation of solitary thyroid nodule (>1 cm diameter) suspicious for malignancy

Table 97.7 Risk factors for gonadal dysfunction following HCT

Table 97.8 Gonadal function in male and female patients following HCT

Chapter 98

Table 98.1 Selected CYP isoenzymes and common inducers, inhibitors, and substrates [1,9,10]

Table 98.2 Selected drug interactions with fluconazole

Table 98.3 Selected drug interactions with voriconazole

Table 98.4 Selected drug interactions with posaconazole

Table 98.5 Selected drug interactions with cyclosporine (CSP)

Table 98.6 Selected drug interactions with tacrolimus

Table 98.7 Selected drug interactions with mycophenolic acid derivatives

Table 98.8 Selected drug interactions with sirolimus

Table 98.9 Selected drug interactions with HMG-CoA reductase inhibitors

Chapter 99

Table 99.1 Contraindicated supplements during HCT

Table 99.2 Nutrient and fluid requirements

Table 99.3 Nutrition intervention strategies for common metabolic complications

Table 99.4 Diet guidelines for immunosuppressed patients

Table 99.5 Nutrition management of common transplant-related oral and gastrointestinal complications

Table 99.6 Gastrointestinal diet progression: the table is an idealized progression and serves as a guideline rather than a rigid regimen

Chapter 100

Table 100.1 Common sources of pain in bone marrow transplantation

Table 100.2 Pain-related education need for hematopoietic cell transplantation (HCT) and their families

Table 100.3 Dosing data for acetaminophen and NSAIDs

Table 100.4 Dose equivalents and starting doses for opioid analgesics

Chapter 101

Table 101.1 Phases of hematopoietic cell transplantation in relation to oral complications and management

Table 101.2 Routine oral hygiene and mucosal care

Table 101.3 Mucositis management

Table 101.4 Management of post-transplantation salivary gland dysfunction

Table 101.5 Topical management of oral chronic graft-versus-host disease

Chapter 102

Table 102.1 Pubertal development in boys given testicular irradiation

Table 102.2 Selected screening recommendations for selected endocrine late effects after HCT in pediatric patients

Chapter 103

Table 103.1 Commonly occurring long-term complications in survivors of hematopoietic cell transplantation

Table 103.2 Key content areas in guidelines for long-term follow-up of survivors

Chapter 104

Table 104.1 Magnitude of risk and populations at increased risk of subsequent malignant neoplasms after hematopoietic cell transplantation

Table 104.2 Magnitude of risk and populations at increased risk of therapy-related leukemia after hematopoietic cell transplantation

Table 104.3 Magnitude of risk and populations at increased of lymphoproliferative disorders after hematopoietic cell transplantation

Table 104.4 Magnitude of risk and populations at increased of solid tumors after hematopoietic cell transplantation

Table 104.5 Magnitude of risk and populations at increased of specific SMNs after hematopoietic cell transplantation

Chapter 105

Table 105.1 Neurologic complications of hematopoietic cell transplantation

Chapter 106

Table 106.1 Summary of vaccine guidelines

List of Illustrations

Chapter 01

Figure 1.1 Survival curves of 70 patients with acute leukemia transplanted with a marrow graft from a histocompatible sibling in Seattle between 1969 and 1974.

Figure 1.2 Survival of 79 patients with Philadelphia chromosome positive acute lymphoblastic leukemia who received high-dose total body irradiation and etoposide followed by allogeneic HCT from HLA-matched sibling donors. At the time of transplantation, 49 patients were in first complete remission and 30 patients were beyond first remission. The outcome is significantly better for patients who were transplanted earlier compared to those who had suffered at least one relapse prior to HCT.

Figure 1.3 Actuarial event-free survival of patients with non-Hodgkin lymphoma treated on the PARMA trial. In this clinical study, the outcome of autologous HCT was compared prospectively to conventional dose chemotherapy. The shown data are based on an intent-to-treat analysis.

Figure 1.4 Kaplan–Meier estimates of event-free survival (EFS) and overall survival (OS) of 35 patients with recurrent or refractory B-cell lymphoma. These patients received autologous transplants and were given two courses of rituximab (4 weekly infusions, 6 weeks and 6 months following transplantation).

Chapter 02

Figure 2.1 Numbers of allogeneic and autologous hematopoietic cell transplantations performed yearly worldwide.

Figure 2.2 Indications for hematopoietic cell transplantation in North America, 2011. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MDS/MPS, myeloproliferative disorder/myelodysplastic syndrome; NHL, non-Hodgkin lymphoma.

Figure 2.3 Annual numbers of allogeneic hematopoietic cell transplantations (HCTs) in the United States reported to the Center for International Blood and Marrow Transplant Research.

Figure 2.4 Incidence of grade III–IV acute graft-versus-host disease (AGVHD), cytomegalovirus (CMV) pneumonia, and 100-day overall mortality, 1-year transplant-related mortality (TRM), and 1-year survival after human leukocyte antigen-identical sibling hematopoietic cell transplantation (HCT) for leukemia among patients reported to the Center for International Blood and Marrow Transplant Research by year of HCT.

Figure 2.5 Causes of death after HLA-identical sibling, unrelated donor, and autologous hematopoietic stem cell transplantations done in 2008–2009. GVHD, graft-versus-host disease; IPn, interstitial pneumonitis.

Chapter 03

Figure 3.1 Scheme for sickle cell anemia correction in mice combining reprogramming, gene transfer and cell therapy. EB, embryoid body; iPS, induced pluripotent stem.

Figure 3.2 Generation of patient-specific human pluripotent cells.

Figure 3.3 Cascade of differentiation from embryonic stem cells (ESCs) to blood cells. CLP, common lymphoid progenitor; CMP, common myeloid progenitor. For other abbreviations, see text.

Figure 3.4 Differentiation of human embryonic stem cells (hESCs) by embryoid body (EB) formation and subsequent analysis of blood progenitor cells appearance via reverse transcriptase polymerase chain reaction (RT-PCR), fluorescence activated cell sorter (FACS), or colony-forming unit (CFU) assay. MEF, mouse embryonic fibroblast.

Chapter 04

Figure 4.1 Hematopoietic lineage tree, showing cells at successive stages of differentiation with distinctive marker profiles (immunophenotypes) in mouse and human. The hematopoietic stem cell (HSC) has long-term reconstituting, self-renewing capacity; the multipotent progenitors have limited or no self-renewal leading to transient but multilineage reconstitution. CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte/erythroid progenitor; GMP, granulocyte/macrophage progenitor; MkP, megakaryocyte progenitor; EP, erythroid progenitor; GP, granulocyte progenitor; MacP, macrophage progenitor; Pro-DC, dendritic cell progenitor; Pro-B, B lymphocyte progenitor; Pro-T, T lymphocyte progenitor; Pro-NK, natural killer cell progenitor.

Figure 4.2 The total number of long-term hematopoietic stem cells (LT-HSCs) in the bone marrow, spleen, and blood of mice on successive days of CY/G-CSF treatment. Total bone marrow hematopoietic stem cells (HSCs) were calculated by assuming that the femurs and tibias (less the epiphyses) contained 15% of all bone marrow in the mouse. Total HSC level in the blood was calculated by assuming that the total blood volume was 1.8 mL. Cell-cycle status of LT-HSCs in the blood was determined by Hoechst DNA staining.

Figure 4.3 Rapid clearance of mobilized hematopoietic progenitor cells from the bloodstream. Clearance from the blood of eGFP+ progenitors and PKH-26+ red blood cells (RBCs), and predicted progenitor and RBC frequencies, respectively. In vivo homing to different organs of mobilized and consecutively transplanted hematopoietic progenitor and stem cells 3 hours after injection.

Figure 4.4 Chimeric analysis of yolk sac blood islands with fluorescent ES clones. Tetrachimeric mice were generated by injection of four distinctly colored single cells into developing blastocysts. The resulting embryos were then analyzed for color combinations observed in the YS and revealed endothelial and hematopoietic cells of different colors in all individual blood islands, indicating that they developed from more than one cell. (a) A chimeric embryo at the early neural plate stage (EB). A white rectangle indicates an immature blood island. The arrow indicates the direction of tissue extension; ec, embryonic ectoderm; me, intra-embryonic mesoderm; ve, visceral endoderm; am, amnion; al, allantois; ch, chorion. (b) Experimental scheme indicating the possible derivations of blood islands and the % of each type observed. (c) A type IV chimeric blood island with EGFP, ECFP, and mRFP1 endothelial cells and ECFP, EGFP, and non-fluorescent hematopoietic cells.

Figure 4.5 At birth, most of the hematopoietic stem cell (HSC) clones in mice are lineage-balanced, that is, equally capable of generating various lineages. However, with age, clones biased towards generating myeloid lineages (myeloid-biased) predominate, due to either clonal selection or epigenetic changes in the originally lineage-balanced clones.

Figure 4.6 Images from Gene Expression Commons (https://gexc.stanford.edu/) showing absolute comparison of the array data for particular genes (EpoR, c-Mpl, IL-7Rα, and c-Ebpα). Raw