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Contents

Contributors

Preface

Part I Pathophysiology of acquired aplastic anemia

1 Stem cell defect in aplastic anemia

Abbreviations

Normal stem cells

Definition

Regulation

The experimental study of primitive hemopoietic cells

Selection of primitive cells by phenotype

How many stem cells get to express themselves?

Aplastic anemia stem cells

Functional assessment of AA hemopoietic progenitor cells

Phenotypic quantitation of AA hemopoietic (CD34+) cells

Assessment of the long-term marrow-repopulating ability of AA hemopoietic cells

Mobilizing potential of AA progenitor cells

Apoptotic properties of AA CD34+ cells

Analysis of telomeric DNA length in AA

Conclusion

References

2 Cytokine abnormalities in aplastic anemia

Introduction

Erythropoietin (EPO)

Granulocyte colony-stimulating factor (G-CSF)

Thrombopoietin (TPO)

Stem cell factor (SCF)

Granulocyte-macrophage colony-stimulating factor (GM-CSF)

Flt-3 ligand (Flt-3L)

Interleukin-1 (IL-1)

Production of cytokines by marrow stromal cells

Rationale for the therapeutic use of cytokines

Conclusion

References

3 Role of T-lymphocytes in the pathophysiology of aplastic anemia

Introduction

Immunophenotyping data on T-cells and natural killer cells in bone marrow and peripheral blood

CD4 and CD8 T-cells

Activated T-cell subpopulation

T-cell receptor VBeta subfamily

Natural killer cells

Markers of T-cell activation

Activation antigens

Cytokine production

Stress proteins

Production of myelosuppressive cytokines by T-lymphocytes

Reactivity of T-lymphocytes against hemopoietic progenitor cells

Evidence of the involvement of an antigen-driven response in the development of AA

Hemopoietic progenitor cells as a target of T-cell attack

Association of certain HLA alleles with a susceptibility to AA

Clonal predominance in T-cell subsets defined by T-cell receptor VBeta expression

Establishment of a T-cell clone reactive to hemopoietic cells from AA patients

Conclusion

References

4 Role of apoptosis in the pathophysiology of aplastic anemia

Introduction

Features of apoptotic cells

Control of apoptosis

Apoptosis: role in immune regulation

Methods of detecting apoptotic cells

Apoptosis in progenitor cells in the bone marrow of those with aplastic anemia

Expression of Fas on normal hemopoietic progenitor cells

Expression of Fas on progenitor cells in aplastic anemia

Modulation of apoptosis by therapeutic intervention

Conclusion

References

5 The interrelation between aplastic anemia and paroxysmal nocturnal hemoglobinuria

Introduction

AA–PNH syndrome – clinical observations

The deficiency of GPI-anchored proteins in AA–PNH syndrome

The GPI anchor and its biosynthesis (reviewed in Rosse, 1997; Socié, 1997)

The most widely studied GPI-anchored proteins (reviewed in Rosse, 1997; Socié, 1997)

The GPI-anchored protein deficiency (reviewed in Rosse, 1997; Socié, 1997)

The GPI-anchored protein deficiency in AA–PNH syndrome

Mutations of the PIG-A gene in AA–PNH syndrome

Molecular biology of the PIG-A gene

Abnormalities of the PIG-A gene in PNH

Abnormalities of the PIG-A gene in AA–PNH syndrome

Conclusion: the mutations of the PIG-A gene as a common genetic basis for PNH and AA–PNH syndrome

References

6 Aplastic anemia and other clonal disorders

Introduction

Clinical observations: the evolution of AA to myelodysplastic syndrome and acute myelogenous leukemia

Studies on clonal hemopoiesis in AA patients using X-linked DNA polymorphisms

Cytogenetic abnormalities in patients with severe aplastic anemia

Conclusion

References

Part II Epidemiology and clinical features of acquired aplastic anemia

7 Epidemiology and etiology of aplastic anemia

Introduction

The role of medical drugs: a good old theory revisited

Environmental and industrial chemicals

Viruses

Risk factors others than exposure

Conclusion

References

8 Clinical presentation, natural course, and prognostic factors

Clinical manifestations

Complementary investigations

Peripheral blood cell counts

Other analytical data

The cytology and histopathology of medullary aplasia

Isotopic investigations of hemopoiesis

Proton magnetic resonance imaging and spectroscopy

Follow-up and survival

Prognosis identification

The prognostic value of symptoms

The prognostic value of peripheral blood cell counts

The prognostic value of the cytology and histopathology of medullary aplasia

The prognostic value of isotope examinations

Statistical prediction models

International criteria

Conclusion

References

Part III Treatment of acquired aplastic anemia

9 Supportive treatment of patients with severe aplastic anemia

Introduction

Prevention and treatment of infections

Risk of infections

Types of infections in SAA patients

Prevention of infections

Antibacterial chemoprophylaxis

Antiviral prophylaxis

Diagnosis of infection

Investigation of fever

Investigation of patients with pulmonary infiltrates

Treatment of infection

Treatment of bacterial infections

Treatment of fungal infections

Treatment of viral infections

Transfusion support

Transfusions and risk for graft rejection after BMT

Alloimmunization after transfusion

Transmission of infectious agents

Transfusion-associated GVHD

Iron overload

Conclusion

References

10 Immunosuppressive treatment of aplastic anemia

Introduction

Lessons from the clinical trials

Effectiveness of ALG

The impact of severity of disease

Cyclosporin

Intensification of immunosuppression

Adjuncts to immunosuppression

Splenectomy

Timing and quality of response

Mechanism of action of ALG and cyclosporin

Treatment schedules

Adverse events of ALG

Immunosuppression in elderly patients

Relapses and nonresponses

New approaches to immunosuppressive treatment

Conclusion

Acknowledgements

References

11 Role of cytokines in the treatment of aplastic anemia

The rationale and potential aims of growth factor treatment in aplastic anemia

Serum/plasma levels and production of endogenous growth factors in aplastic anemia

Clinical trials of hemopoietic growth factors in aplastic anemia

Granulocyte colony-stimulating factor

Granulocyte/macrophage colony-stimulating factor (GM-CSF)

Erythropoietin

Interleukin-3 (IL-3)

Interleukin-1 (IL-1)

Interleukin-6 (IL-6)

Stem-cell factor (SCF)

Conclusion

References

12 HLA-identical sibling bone marrow transplantation to treat severe aplastic anemia

Introduction

HLA-identical sibling transplants

Survival, current results, and trends over time

Engraftment

Hemopoietic chimerism

Acute GVHD

Chronic GVHD

Interstitial pneumonitis

Late complications

The influence of SAA etiology on outcome

Syngeneic transplants

HLA-phenotypically identical donors

Conclusion

References

13 Alternative donor bone marrow transplantation for severe acquired aplastic anemia

Introduction

Prognostic factors for HLA-identical sibling BMT

Partially matched family donor BMT: early experience

HLA-matched unrelated donor BMT: early experience

Analysis of factors affecting outcome of alternative donor BMT

Patients and methods

Patient population

Donor population and HLA matching

Transplant data

Outcomes analyzed

Statistical methods

Results

Survival

Engraftment

Acute GVHD

Chronic GVHD

Cause of death

Discussion

Future directions

Transfusion policy in patients with SAA

HLA molecular epitope analysis

Conclusion

References

14 Treatment of children with acquired aplastic anemia

Introduction

BMT from HLA-identical siblings

BMT from alternative donors

Immunosuppressive treatment

Hemopoietic growth factors

Late effects on children

Treatment results obtained in the last 5 years in Europe

Conclusion

References

15 Long-term follow-up of patients with aplastic anemia: clonal malignant and nonmalignant complications

Introduction

Historical background

Secondary MDS or leukemia

New solid cancers

Paroxysmal nocturnal hemoglobinuria

Conclusion

References

16 Guidelines for treating aplastic anemia

Decision making: immunosuppressive treatment versus allogeneic bone marrow transplantation as first-line treatment of…

Bone marrow transplantation

HLA-matched sibling transplantation

Unrelated and family-mismatched donor transplants

Immunosuppressive treatment

Failures to respond to first-line treatment/relapse

Failures to respond to second-line treatment

Age limit for immunosuppressive treatment

Myelodysplastic syndrome/leukemia after treatment

Conclusion

Part IV Fanconi’s anemia

17 Clinical features and diagnosis of Fanconi’s anemia

Clinical suspicion of Fanconi’s anemia

Diagnosis of FA

Hematological manifestations

Leukemia

Myelodysplastic syndrome

Cancer

Liver disease

Reproduction

Prognosis

Conclusion

References

18 Genetic basis of Fanconi’s anemia

Introduction

Cellular phenotypes

Genetic heterogeneity

Identification of the FA genes

Cloning of FANCC

Function of FANCC

Patterns of FANCC and fancc expression

Cloning of FANCA

The basic defect of the various complementation groups

Animal models

Conclusion

Acknowledgements

References

19 Treatment of Fanconi’s anemia

Introduction

HLA-identical sibling bone marrow transplants

Alternative donor transplants

New strategies

Cord blood transplant

Gene therapy

Conclusion

References

20 Genetic correction of Fanconi’s anemia

Introduction

FANCC and FANCA

Hemopoietic defect in FA

FA gene transduction and hemopoiesis

Hemopoietic stem cell targets and rationale for gene therapy

NIH experimental trial of FANCC gene therapy

Lessons from the NIH trial

Conclusion

References

Index