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Page 1: Hematopoietic Stem Cell Transplantation fileContents 1 Principles and Overview of Allogeneic Hematopoietic Stem Cell Transplantation ..... 1 Sergio Giralt and Michael R. Bishop

Hematopoietic Stem Cell Transplantation

Page 2: Hematopoietic Stem Cell Transplantation fileContents 1 Principles and Overview of Allogeneic Hematopoietic Stem Cell Transplantation ..... 1 Sergio Giralt and Michael R. Bishop

Cancer Treatment and ResearchSteven T. Rosen, M.D., Series Editor

Bishop, M.R. (ed): Hematopoietic Stem Cell Transplantation. 2009. ISBN 978-0-387-78579-0.

Blake, M., Kalra, M. (eds): Imaging in Oncology. 2008. ISBN 978-0-387-75586-1.

Gradishar, W.J., Wood, W.C. (eds): Advances in Breast Care Management, Second Edition. 2008.

978-0-387-73160-5.

Ansell, S. (ed): Rare Hematological Malignancies. 2008. ISBN 978-0-387-73743-0.

Angelos, P. (ed): Ethical Issues in Cancer Patient Care, Second Edition. 2008.

ISBN 978-0-387-73638-9.

Woodruff, T., Snyder, K.A. (eds): Oncofertility. 2007. ISBN 978-0-387-72292-4.

Raizer, J., Abrey, L.E. (eds): Brain Metastases. 2007. ISBN 978-0-387-69221-0.

Leong, S.P.L. (ed): Cancer Metastasis and the Lymphovascular System: Basis for rational therapy.

2007. ISBN 978-0-387-69218-0.

Ceelen, W.P. (ed): Peritoneal Carcinomatosis: A Multidisciplinary Approach. 2007.

ISBN 978-0-387-48991-9.

Meyers, C. (ed): Aids-Associated Viral Oncogenesis. 2007. ISBN 978-0-387-46804-4.

Leong, S.P.L. (ed): Cancer Clinical Trials: Proactive Strategies. 2006. ISBN 0-387-33224-3.

Leonard, J.P., Coleman, M. (eds): Hodgkin’s and Non-Hodgkin’s Lymphoma. 2006.

ISBN 0-387-29345.

Haefner, B., Dalgleish, A. (eds): The Link Between Inflammation and Cancer. 2006.

ISBN 0-387-26282-2.

Small, Jr. W., Woloschak, G. (eds): Radiation Toxicity: A Practical Guide. 2005.

ISBN 1-4020-8053-0.

Leong, S.P.L., Kitagawa, Y., Kitajima, M. (eds): Selective Sentinel Lymphadenectomy for Human

Solid Cancer. 2005. ISBN 0-387-23603-1.

Platanias, L.C. (ed.): Cytokines and Cancer. 2005. ISBN 0-387-24360-7.

Abrey, L.E., Chamberlain, M.C., Engelhard, H.H. (eds): Leptomeningeal Metastases. 2005.

ISBN 0-387-24198-1

Balducci, L., Extermann, M. (eds): Biological Basis of Geriatric Oncology. 2004. ISBN

Khleif, S. (ed.): Tumor Immunology and Cancer Vaccines. 2004. ISBN 1-4020-8119-7.

Farid, N. (ed.): Molecular Basis of Thyroid Cancer. 2004. ISBN 1-4020-8106-5.

Finn, W.G., Peterson, L.C. (eds.): Hematopathology in Oncology. 2004. ISBN 1-4020-7919-2.

Verweij, J., Pinedo, H.M. (eds): Targeting Treatment of Soft Tissue Sarcomas. 2004.

ISBN 1-4020-7808-0.

Kumar, R. (ed.): Molecular Targeting and Signal Transduction. 2004. ISBN 1-4020-7822-6.

Keller, E.T., Chung, L.W.K. (eds): The Biology of Skeletal Metastases. 2004. ISBN 1-4020-7749-1.

For further volumes:

http://www.springer.com/5808

Page 3: Hematopoietic Stem Cell Transplantation fileContents 1 Principles and Overview of Allogeneic Hematopoietic Stem Cell Transplantation ..... 1 Sergio Giralt and Michael R. Bishop

Michael R. BishopEditor

Hematopoietic Stem CellTransplantation

1 3

Page 4: Hematopoietic Stem Cell Transplantation fileContents 1 Principles and Overview of Allogeneic Hematopoietic Stem Cell Transplantation ..... 1 Sergio Giralt and Michael R. Bishop

Editor

Michael R. BishopNational Cancer InstituteBethesda, MD, [email protected]

ISSN: 0927-3042ISBN: 978-0-387-78579-0 e-ISBN: 978-0-387-78580-6DOI 10.1007/978-0-387-78580-6

Library of Congress Control Number: 2008921984

# Springer ScienceþBusiness Media, LLC 2009All rights reserved. This workmay not be translated or copied in whole or in part without the writtenpermission of the publisher (Springer ScienceþBusinessMedia, LLC, 233 Spring Street, NewYork,NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use inconnection with any form of information storage and retrieval, electronic adaptation, computersoftware, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if theyare not identified as such, is not to be taken as an expression of opinion as to whether or not they aresubject to proprietary rights.While the advice and information in this book are believed to be true and accurate at the date ofgoing to press, neither the authors nor the editors nor the publisher can accept any legalresponsibility for any errors or omissions that may be made. The publisher makes no warranty,express or implied, with respect to the material contained herein.

Printed on acid-free paper

springer.com

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Contents

1 Principles and Overview of Allogeneic Hematopoietic Stem Cell

Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Sergio Giralt and Michael R. Bishop

2 The Principles and Overview of Autologous Hematopoietic Stem Cell

Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23William Vaughan, Tara Seshadri, Mark Bridges,and Armand Keating

3 Natural Killer Cell Activity and Killer Immunoglobulin-Like Receptors

in Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . 47Loredana Ruggeri, Shuhong Zhang, and Sherif S. Farag

4 Advancement and Clinical Implications of HLA Typing in Allogeneic

Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . 71Lee Ann Baxter-Lowe and Carolyn Katovich Hurley

5 Immunogenomics and Proteomics in Hematopoietic Stem Cell

Transplantation: Predicting Post-Hematopoietic Stem Cell

Transplant Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Eva M. Weissinger and Anne M. Dickinson

6 Clinical Implications of Immune Reconstitution Following

Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . 131Karl S. Peggs, Aviva C. Krauss and Crystal L. Mackall

7 Functionally Defined T Cell Subsets in Transplantation Biology

and Therapy: Regulatory T Cells and Th2 Cells. . . . . . . . . . . . . . . . . 155Daniel Fowler, Petra Hoffmann, and Matthias Edinger

8 Understanding and Enhancing the Graft-Versus-Leukemia Effect

After Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . 187Jeffrey Molldrem and Stanley Riddell

v

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9 Reduced-Intensity and Nonmyeloablative Conditioning Regimens . . . 209Francine Foss and Koen van Besien

10 Umbilical Cord Blood Transplantation. . . . . . . . . . . . . . . . . . . . . . . . 233John E. Wagner, Claudio Brunstein, William Tse,and Mary Laughlin

11 Biology and Management of Acute Graft-Versus-Host Disease . . . . . 257Robert Korngold and Joseph H. Antin

12 Biology and Management of Chronic Graft-Versus-Host Disease . . . 277Paul J. Martin and Steven Z. Pavletic

13 Radioimmunoconjugates in Hematopoietic Stem Cell

Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Ajay K. Gopal and Jane N. Winter

14 Evolving Indications for Hematopoietic Stem Cell Transplantation

in Multiple Myeloma and Other Plasma Cell Disorders. . . . . . . . . . . 317Guido Tricot, Maurizio Zangari, Roberto Sorasio,and Benedetto Bruno

15 Role of Hematopoietic Stem Cell Transplantation in the Treatment

of Non-Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357Philip J. Bierman and Gordon L. Phillips

16 The Role of Hematopoietic Stem Cell Transplantation in Hodgkin

Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399Craig Moskowitz and John Sweetenham

17 Role of Hematopoietic Stem Cell Transplantation in Acute

Myelogenous Leukemia and Myelodysplastic Syndrome . . . . . . . . . . 415Martin S. Tallman, Vikram Mathews, and John F. DiPersio

18 Allogeneic Hematopoietic Stem Cell Transplantation for Adult

Acute Lymphoblastic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441Daniel Weisdorf and Stephen Forman

19 Hematopoietic Stem Cell Transplantation in Children

and Adolescents with Malignant Disease . . . . . . . . . . . . . . . . . . . . . . 455Mitchell S. Cairo and Thomas G. Gross

20 Cellular Adoptive Immunotherapy After Autologous and Allogeneic

Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . 497David L. Porter, Elizabeth O. Hexner, Sarah Cooley,and Jeffrey S. Miller

vi Contents

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21 Improvements in the Prevention and Management of Infectious

Complications After Hematopoietic Stem Cell Transplantation . . . . . 539Juan C. Gea-Banacloche and James C. Wade

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

Contents vii

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Introduction

The dogmas of the quiet past are inadequate to the stormy present. The occasion ispiled high with difficulty, and we must rise with the occasion. As our case is new, so wemust think anew and act anew.

Abraham Lincoln, 1862

When I came across this quote, it made me recall my first participation at aninternational meeting on bone marrow transplantation, at a time when this wasthe only term that was used to describe the field. During a particular sessionthere was a presentation on the use of peripheral blood as the sole source of stemcells for transplantation, and a member of the audience rose to state that it wasmedically unethical to consider such treatment, as it certainly could not containstem cells. Now nearly twenty years later, peripheral blood is the predominantsource of stem cells used for hematopoietic stem cell transplantation. In thesame period of time there have been several other dogmatic opinions, whichpermeate all of medicine, that have come and gone in the field of hematopoieticstem cell transplantation, and will continue to do so with advancements frombasic and clinical research.

It is within this context that the format of this book was devised.Traditionally reviews on specific topics related to hematopoietic stem celltransplantation reflect the views of a single author or a research group.Although that view may be correct, it is rare within this field that the view isuniversally accepted, and with continued advances in research, opinions andviews are quickly challenged or disproved. As such, each chapter within this textis authored by at least two individuals, both respected authorities on theirrespective topic, who do not necessarily share the same opinion or have directresearch ties. The goal was to bring two perspectives to the same topic resultingin a more comprehensive and balanced review on relevant topics related to thefield of hematopoietic stem cell transplantation. The danger in using such anapproach was either a predominant review of one author or a particularlysanitized presentation on only areas where the authors had total agreementwould emerge. However, the results of this ‘‘little experiment’’ were quitepleasing, as the reader will find in the following chapters contained within thistext. They offer broad and often contrasting opinions on specific topics,highlighting the expertise of all the authors. More often than not, the

ix

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collaboration between the various authors, who had not worked togetherpreviously, resulted in truly unique reviews.

The topics covered within this text cover general principles of hematopoieticstem cell transplantation, application of hematopoietic stem celltransplantation to specific diseases, and the biology and treatment oftransplant-related complications. In addition specific chapters cover topics inwhich further understanding of the underlying biology and advancementswithin the laboratory or emerging topics which are currently or likely havingmajor clinical implications on the field filed of hematopoietic stem celltransplantation.

This collection is meant to complement more encyclopedic texts on thesubject of hematopoietic stem cell transplantation. Each chapter is moredetailed than a standard review, yet adequately concise and focused toprovide comprehensive information relative to biology, clinical results, andtreatment recommendations to meet the needs of students, scientists, andclinicians interested in the field of hematopoietic stem cell transplantation. Itis hoped that those needs will be met and result in the improved care andoutcomes of patients undergoing hematopoietic stem cell transplantation.

Michael R. Bishop, M.D.

x Introduction

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Contributors

Joseph H. AntinThe Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA,[email protected]

Lee Ann Baxter-LoweDepartment of Surgery, University of California, San Francisco, CA, USA,[email protected]

Philip J. BiermanDepartment of Internal Medicine, Section of Oncology-Hematology,University of Nebraska Medical Center, 987680 Nebraska Medical Center,Omaha, NE, USA, [email protected]

Michael R. BishopExperimental Transplantation and Immunology Branch, National CancerInstitute, Bethesda, MD, USA, [email protected]

Mark BridgesUniversity of Alabama Bone Marrow Transplantation Program, University ofAlabama Comprehensive Cancer Center Birmingham, Alabama, USA

Claudio BrunsteinUniversity of Minnesota, Minneapolis, Minnesota, USA

Benedetto BrunoAssistant Professor of Hematology, Bone Marrow Transplantation UnitProgramHead University of Torino, Italy School ofMedicine, [email protected]

Mitchell S. CairoMorgan Stanley Children’s Hospital of New York-Presbyterian, ColumbiaUniversity, Columbus, OH, USA, [email protected]

Sarah CooleyDivision of Hematology, Oncology and Transplantation, University ofMinnesota Cancer Center, Minneapolis, MN 55445

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Anne M. DickinsonNewcastle University, [email protected]

John F. DiPersioDivision of Oncology, Siteman Cancer Center, Washington University Schoolof Medicine, St Louis, MO, USA, [email protected]

Matthias EdingerDepartment of Hematology and Oncology, University Hospital Regensburg,Regensburg, Germany, [email protected]

Sherif S. FaragDivision ofHematology andOncology, IndianaUniversity School ofMedicine,Indianapolis, IN, USA, [email protected]

Stephen FormanThe City of Hope National Medical Center, Duarte, CA, USA,[email protected]

Francine FossMedical Oncology and Bone Marrow Transplantation, Yale University Schoolof Medicine, New Haven, CT, USA, [email protected]

Daniel FowlerExperimental Transplantation and Immunology Branch, Center for CancerResearch, National Cancer Institute, Bethesda, MD, USA,[email protected]

Juan C. Gea-BanaclocheExperimental Transplantation and Immunology Branch, National CancerInstitute, National Institutes of Health, Bethesda, MD, USA,[email protected]

Sergio GiraltM.D. Anderson Cancer Center, Houston, TX, USA, [email protected]

Ajay K. GopalDivision of Medical Oncology, Department of Medicine, University ofWashington and Clinical Research Division, Fred Hutchinson CancerResearch Center, Seattle, WA, USA, [email protected]

Thomas G. GrossNationwide Children’s Hospital, Ohio State University, Columbus, OH, USA,

Elizabeth O HexnerDivision of Hematology-Oncology and Abramson Cancer Center, Universityof Pennsylvania Medical Center, Philadelphia, PA 19106

Petra HoffmannDepartment of Hematology and Oncology, University Hospital Regensburg,Regensburg, Germany

xii Contributors

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Carolyn Katovich HurleyDepartment of Oncology, Georgetown University Medical Center,Washington, DC, USA, [email protected]

Armand KeatingDepartment of Hematology and Medical Oncology, Princess MargaretHospital, Toronto, Ontario, Canada, [email protected]

Robert KorngoldThe Cancer Center, Hackensack University Medical Center, Hackensack, NJ,USA, [email protected]

Aviva C. KraussPediatric Oncology Branch, National Cancer Institute, NIH Bethesda,Maryland, USA

Mary LaughlinCase Western Reserve University, Cleveland, OH, USA, [email protected]

Crystal L. MackallPediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD,USA, [email protected]

Paul J. MartinFred Hutchinson Cancer Research Center, Seattle, WA, USA,[email protected]

Vikram MathewsDepartment of Haematology, Christian Medical College, Vellore,India 632004

Jeffrey S. MillerDivision of Hematology, Oncology and Transplantation, University ofMinnesota Cancer Center, Minneapolis, MN, USA, [email protected]

Jeffrey MolldremTransplant Immunology, M.D. Anderson Cancer Center, Houston, TX, USA,[email protected]

Craig MoskowitzMemorial Sloan-Kettering Cancer Center, New York, NY, USA,[email protected]

Steven Z. PavleticExperimental Transplantation and Immunology Branch, National CancerInstitute, Bethesda, MD, USA, [email protected]

Karl S. PeggsRoyal Free and University College London Medical Schools, London, UK,[email protected]

Contributors xiii

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Gordon L. Phillips IIWilmot Cancer Center, Department of Medicine, University ofRochester Medical Center, Rochester, NY, USA,[email protected]

David L. PorterDivision of Hematology-Oncology and Abramson Cancer Center, Universityof Pennsylvania Medical Center, Philadelphia, PA, USA,[email protected]

Stanley RiddellClinical Research Division, Fred Hutchinson Cancer Research Center,Professor of Medicine, University of Washington, Seattle, WA, USA,[email protected]

Loredana RuggeriUniversity of Perugia, Perugia, Italy, [email protected]

Tara SeshadriDepartment of Hematology and Medical Oncology Princess MargaretHospital, Toronto, Ontario, Canada

Roberto SorasioChief Resident University of Torino, Italy School of Medicine

John SweetenhamTaussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA,[email protected]

Martin S. TallmanDivision of Hematology-Oncology, Northwestern University Feinberg Schoolof Medicine, Chicago, IL, USA, [email protected]

Guido TricotUniversity of Utah School of Medicine, [email protected]

William TseCase Western Reserve University, Cleveland, Ohio, USA.

Koen van BesienSection of Hematology/Oncology, University of Chicago, Chicago, IL, USA,[email protected]

William VaughnUniversity of Alabama Bone Marrow Transplantation Program, Universityof Alabama Comprehensive Cancer Center, Birmingham, AL, USA,[email protected]

James C. WadeMedical College of Wisconsin, Milwankee, WI, USA, [email protected]

xiv Contributors

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John E. WagnerUniversity of Minnesota, Minneapolis, MN, USA,[email protected]

Daniel WeisdorfUniversity of Minnesota Blood and Marrow Transplant Program,Minneapolis, MN, USA, [email protected]

Eva M. WeissingerHannover Medical School, [email protected]

Jane N. WinterDivision of Hematology/Oncology, Department of Medicine, and Robert H.Lurie Comprehensive Cancer Center, Feinberg School of Medicine,Northwestern University, Chicago, IL, USA, [email protected]

Maurizio ZangariProfessor of Medicine, University of Utah School of Medicine

Shuhong ZhangDivision of Hematology and Oncology, Indiana University School ofMedicine Indianapolis, Indiana, U.S.A.

Contributors xv

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Chapter 1

Principles and Overview of Allogeneic

Hematopoietic Stem Cell Transplantation

Sergio Giralt and Michael R. Bishop

1.1 Introduction and Historical Perspectives

Hematopoietic stem cell transplantation (HSCT) is the process and intravenousinfusion of hematopoietic stem and progenitor cells to restore normal hematopoiesisand/or treat malignancy [1, 2]. The term ‘‘hematopoietic stem cell transplantation’’has replaced the term ‘‘bonemarrow transplantation’’ (BMT) because hematopoieticstem cells can be derived from a variety of sources other than the bone marrow,including the peripheral blood and umbilical cord blood [2, 3]. Stem cells used forHSCT are distinguished as being of hematopoietic origin, as there is growinginterest in using more primitive stem cells for regenerative therapy due to theirplasticity and unique biologic characteristics [4]. Hematopoietic stem cells arefurther characterized according to their source, that is, from whom they areobtained. Hematopoietic stem cells obtained from the patient him- or herselfare referred to as autologous [1, 3]. Hematopoietic stem cells obtained from anidentical twin are referred to as syngeneic obtained, and hematopoietic stemcells from someone other than the patient or an identical twin are referred toas allogeneic, which is the focus of this chapter.

The clinical application of HSCT originated in the clinical observations of thesevere myelosuppressive effects of radiation among nuclear bomb survivors atHiroshima and Nagasaki [5]. Intensive research efforts were made in the 1950sand early 1960s to develop methods to reverse the myelosuppressive effects ofradiation, including the infusion of bone marrow [6–11]. The subsequent determi-nation and understanding of the major histocompatibility complex (MHC) andhuman leukocyte antigens (HLA) as the major determinants of graft rejectionsignificantly advanced laboratory studies and clinical application of allogeneicHSCT [12–14]. The first successful reports of clinical bonemarrow transplantation,utilized for patients with severe combined immunodeficiency disorders, severeaplastic anemia, and advanced acute leukemias, occurred in the late 1960s and

S. Giralt (*)M.D. Anderson Cancer Center, Houston, TX, USAe-mail: [email protected]

M.R. Bishop (ed.), Hematopoietic Stem Cell Transplantation,Cancer Treatment and Research 144, DOI 10.1007/978-0-387-78580-6_1,� Springer ScienceþBusiness Media, LLC 2009

1

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early 1970s [15–20]. Allogeneic HSCT has become a standard treatment option fora variety of hematologic malignancies (Table 1.1) [21]. In addition, allogeneicHSCT is a standard treatment for many immunodeficiency states, metabolicdisorders (e.g., Hurler‘s syndrome), and defective hematopoietic states (e.g., severeaplastic anemia, thalassemia). This chapter focuses primarily on the rationale forthe application of allogeneic HSCT in the treatment of malignancy.

The distinctive characteristics of allogeneic HSCT are that the stem cell graft isfree of contamination bymalignant cells and contains immunologically competentlymphocytes that are capable ofmediating a reaction against foreign antigens. Thislatter characteristic can be a major advantage if the immunologic response isdirected against malignant cells, referred to as the graft-versus-leukemia or graft-versus-tumor (GvT) effect, thus potentially eradicating disease and reducing thechance of disease relapse [22–24]. However, if the immunologic response is directedagainst antigens present on normal tissues, it can lead to the destruction of normalorgans, described clinically as graft-versus-host disease (GvHD). The risk of bothgraft rejection (host-versus-graft reaction) and GvHD rises with HLA disparity.

The GvT effect was first recognized in animal models and subsequently wasnoted among patients undergoing allogeneic HSCT for acute and chronicleukemias [22–25]. The clinical importance of the interactions between immu-nocompetent donor T cells and tumor cells inmediating aGvT effect is supportedby an increased rate of relapse in allogeneic stem cell grafts from which T cells

Table 1.1 Clinical indications for allogeneic hematopoietic stemcell transplantation

Malignant disorders

Acute myeloid leukemia

Acute lymphoblastic leukemia

Chronic myeloid leukemia

Myelodysplastic syndromes

Myeloproliferative disorders

Non-Hodgkin‘s lymphoma

Hodgkin‘s disease

Chronic lymphocytic leukemia

Multiple myeloma

Juvenile chronic myeloid leukemia

Non-malignant disorders

Aplastic anemia

Paroxysmal nocturnal hemoglobinuria

Fanconi‘s anemia

Blackfan–Diamond anemia

Thalassemia major

Sickle cell anemia

Severe combined immunodeficiency

Wiskott–Aldrich syndrome

Inborn errors of metabolism

Modified from Copelan EA. N Engl J Med. 2006;354:1813–26

2 S. Giralt and M.R. Bishop

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have been removed (T-cell depletion), an inverse correlation between relapse andseverity of GvHD, and a comparatively increased rate of relapse after syngeneicor autologous HSCT using the same myeloablative conditioning regimen [25].Finally, the most compelling evidence for a T cell-mediated GvT effect originatesfrom the observation that infusion of allogeneic lymphocytes, a donor lympho-cyte infusion (DLI), at a time remote from the transplant conditioning regimen,can treat leukemia relapse successfully after allogeneic HSCT [26–29]. The DLI,without any additional cytotoxic therapy, resulted in sustained cytogenetic andmolecular remissions. Over time it became increasingly apparent that a signifi-cant part of the curative potential of allogeneicHSCT could be directly attributedto the GvT effect.

1.2 Technical Aspects of Allogeneic Hematopoietic Stem Cell

Transplantation

1.2.1 Donor Selection

In allogeneic HSCT, stem cells are obtained from a donor other than therecipient. Donor and recipient usually are identical or ‘‘matched’’ for HLA,which is derived from the MHC located on chromosome 6 [30]. A single set ofMHC alleles, described as a haplotype, is inherited from each parent, resultingin HLA pairs. The most important HLAs include HLA-A, HLA-B, HLA-C,HLA-DR, and HLA-DQ loci. Among siblings, the genes which encode forHLA-B and HLA-C are located so close to each other in the MHC that one israrely inherited without the other. As a result, an HLAmatch among siblings isreferred to a ‘‘6 of 6,’’ as they are matched for HLA-A, -B, and -DR; however, inactuality they are matched for all of the HLA antigens [3]. The other antigens,such as HLA-C, become more important in alternative sources of hematopoie-tic stem cells, such as unrelated donors and cord blood, which are described inmore detail later in this chapter [31, 32].

The choice of donor for an allogeneic HSCT takes into account severalfactors, including the patient‘s disease, disease state, and urgency in obtaininga donor. When allogeneic HSCT is being considered for a patient, a fully HLA-matched sibling is the preferred donor source, because the risk of graft rejectionand GvHD is lowest with this source of allogeneic stem cells. As describedearlier, a haplotype is inherited from each parent, and by simple Mendeliangenetics it would be expected that the probability that two siblings would sharethe same haplotypes would be 1:4. The probability of having an HLA-matchedsibling increases with the number of siblings within a specific family. Theprobability can be estimated using the following formula: The chance of havingan HLA-matched sibling=1–(0.75)n, where n is the number of potential siblingdonors [3]. There is an approximately 1% chance of crossing over (i.e., geneticmaterial switched between chromosomes during meiosis), primarily between

1 Principles and Overview of Allogeneic Hematopoietic Stem Cell Transplantation 3

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the HLA-A and the HLA-B loci. The clinical outcomes for allogeneic HSCTusing a sibling with a single HLA mismatch are similar to those with a fullyHLA-matched sibling [33].

For patients who lack a fully HLA-matched sibling donor, the preferred alter-native sources for allogeneic stem cells include an unrelated fully HLA-matcheddonor, a partially HLA-matched cord blood unit, or a partially HLA-matchedfamilymember [34–36]. A closelyHLA-matched volunteer hematopoietic stem celldonor may be identified through a bone marrow donor registry, such as theNational Marrow Donor Program (NMDP) in the United States, which includesabout six million potential donors. Many HLA phenotypes are possible, whichsometimesmakes the identification of amatched unrelated donor difficult and timeconsuming. Depending on the ethnic descent of both patient and donor, theprobability of identifying an HLA-matched unrelated donor is between 50% and80%. Due to advances in HLA-typing (reviewed in Chap. 4 by Baxter-Lowe andHurley) through the use of molecular typing techniques and improved supportivecare over the last decade, current results of matched unrelated donor transplantsfor malignancy are not significantly different when compared to HSCT frommatched sibling donor transplant [32, 37].

One major disadvantage of using an unrelated donor is that the average timerequired to identify and procure an HLA-matched unrelated donor is approxi-mately 2–3 months, which may be too long for patients with rapidly progressivemalignancies [38]. The alternative stem cell source to an unrelated bone marrowdonor for allogeneic HSCT is umbilical cord blood [35–39]. The major advan-tages of umbilical cord stem cells (reviewed in Chap. 10 by Wagner, Brunstein,Tse, and Laughlin) is that they can be obtained in less than 4 weeks and thateven cord blood units mismatched in up to 2 of 6 HLA may be used forallogeneic HSCT. This degree of HLA mismatching is acceptable because theoverwhelming percentage of T cells within the cord blood unit are naıve, and theincidence of acute GvHD is comparable to or less than that associated with anHLA-matched unrelated bone marrow donor. The major disadvantage ofumbilical cord blood units is they are associated with a relatively high degreeof graft rejection, especially in adults [35, 39]. Engraftment and treatment-related mortality appear to be directly related to umbilical cord cell dose; thesmall volume usually available (50–150 mL) of cord blood results in low stemcell doses in adult patients. It may be that the limitation of cell dose can beovercome by the use of more than one cord blood unit or the transient supportfrom CD34+ cells from haploidentical family members [40, 41]. The othersignificant disadvantage is that once the cord blood unit is used, there is noway to go back and get additional cells for a donor lymphocyte infusion or inthe event of graft failure.

The other alternative source of allogeneic hematopoietic stem cells is toidentify partially HLA-matched family among the patient‘s first-degree rela-tives who share at least one haplotype (haploidentical) with the potentialrecipient [36, 42]. The major advantage with the use of a haploidentical familymember is that the donor is readily available for almost all patients. The major

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disadvantages are an increased risk of graft rejection, GvHD, and severeimmune dysregulation, which rises with higher degrees of HLA-mismatching.Haplo-identical allogeneic HSCT has been limited primarily to use in children,although the use of less intense conditioning regimens (discussed below) hasincreased its applicability in adults [36, 43].

1.2.2 Stem Cell Acquisition

Hematopoietic stem cells for allogeneic HSCT may be obtained from the bonemarrow, the peripheral blood, and umbilical cord blood. Bone marrow hema-topoietic stem cells usually are harvested by repeated aspirations from theposterior iliac crest until an adequate number of cells have been removed [44].If sufficient cells cannot be obtained from the posterior iliac crest, marrow alsocan be harvested from the anterior iliac crest and sternum. Theminimal numberof nucleated marrow cells required for long-term repopulation in humans is notprecisely known. In practice, the number of nucleated marrow cells harvested isusually 1–3�108/kg of recipient weight, depending on the diagnosis (i.e., higherfor aplastic anemia), the type and intensity of pre-transplant conditioning, andwhether the marrow graft will be modified in vitro. Marrow sometimes istreated in vitro to remove unwanted cells before it is returned to the patient.In allogeneic HSCT with major ABO incompatibility between donor andrecipient, it is necessary to remove the mature erythrocytes from the graft toavoid a hemolytic transfusion reaction [45]. Peripheral blood hematopoieticstem cells are used in approximately 60–70% of allogeneic HSCT [46]. Insteady-state, the concentration of hematopoietic stem cells and myeloid pro-genitor cells is quite low, and prior to collection of peripheral blood hemato-poietic stem cells by apheresis, attempts are made to increase or ‘‘mobilize’’ thenumber of circulating hematopoietic stem cells by administering hematopoieticgrowth factors, primarily granulocyte colony-stimulating factor (G-CSF; fil-grastim) to the donor. The procedure is associated with a very low incidence ofcomplications and can generally be done as an outpatient. In both the auto-logous and the allogeneic settings, the use of peripheral blood stem cells hasbeen associated with accelerated recovery of hematopoiesis when compared totraditional BMT. In the allogeneic setting, the presence of higher numbers of Tcells in the peripheral blood stem cell graft initially raised the concern forgreater frequency and severity of GvHD. Several large studies have nowdemonstrated that the use of peripheral blood in the allogeneic HSCT settingis associated with a decreased relapse rate in hematologic malignancies andimprovement in overall and disease-free survival in patients with late-stagedisease [47]. However, the use of peripheral blood has been associated with asignificant risk of extensive chronic GvHD. After collection and processing,hematopoietic stem cells from bone marrow, peripheral blood, or cord bloodmay be directly infused or they may be processed with dimethylsulfoxide

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(DMSO) with or without hydroxyethylstarch and then stored in liquid nitrogenuntil needed for transplantation [48].

1.2.3 Conditioning

Once an allogeneic stem cell source has been identified, patients are put onregimens with the intent of ‘‘conditioning’’ or ‘‘preparing’’ them for the infusionof hematopoietic stem cells. Most conditioning or preparative regimens use acombination of radiation and chemotherapy [1, 3]. They also may containradio-immunoconjugates and/or monoclonal antibodies that target T cells(e.g., alemtuzumab) [49]. The choice of a specific conditioning regimen dependson the disease that is being treated. The earliest conditioning regimens weredesigned to permit the administration of maximum doses of chemotherapy and/or radiation (i.e., ‘‘high-dose’’ regimens) for the eradication of disease and to beadequately immunosuppressive to prevent graft rejection. The most commonlyused chemotherapy agents in these regimens are alkylating agents (e.g., cyclo-phosphamide and/or etoposide) with or without total lymphoid or total bodyirradiation (TBI) at doses varying between 800 and 1440 cGy. The doses ofchemotherapy and radiation used in these regimens are referred to as ‘‘myeloab-lative’’ because they result in a degree of myelosuppression and immunosup-pression that is nearly universally fatal without the infusion of hematopoieticstem cells as a rescue product [50].

Though efficacious, TBI is associated with a number of short and long-termcomplications including secondary malignancies, cataracts, and endocrine dys-function.More recently a low-dose non-fractionated mode of administration ofTBI with 200 cGy has been incorporated in the setting of nonmyeloablativetransplants [51]. The toxicities of TBI-containing conditioning regimens led tothe development of radiation-free regimens. Of these, the most commonly usedchemotherapy is the combination of busulfan and cyclophosphamide, devel-oped initially by Santos and coworkers and subsequently modified by Tutschkaet al. [52, 53]. Busulfan is traditionally administered orally as 4mg/kg divi-ded into four daily doses and given on each of four successive days (totaldose¼ 16�mg/kg) but this oral administration is limited by the erratic absorp-tion of the drug. High plasma levels are associated with increased incidence ofhepatic veno-occlusive disease (VOD) and other toxicities [53]. More recently,an intravenous formulation of busulfan has become available which allowsmore predictable drug delivery [54].

Allogeneic HSCT with myeloablative conditioning regimens has been per-formed successfully in patients older than 60 years of age; however, survivalafter these transplants declines with increasing age, limiting the application ofallogeneic transplantation to a minority of patients who potentially couldbenefit from this procedure. The substantial toxicities associated with tradi-tional, myeloablative conditioning regimens have limited the application of

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allogeneic transplantation to relatively young patients with good performancestatus. However, the demonstration that an immune-mediated GvT effect playsa central role in the therapeutic efficacy of allogeneic HSCT led to the hypoth-esis that myeloablative conditioning regimens were not essential for tumoreradication. This idea subsequently led investigators to develop less intense,‘‘nonmyeloablative’’ conditioning regimens, which were adequately immuno-suppressive to permit the engraftment of donor hematopoietic stem cells, whilesparing the patient many of the toxicities related to traditional high-dosetherapy. A variety of nonmyeloablative and ‘‘reduced-intensity’’ conditioningregimens have been reported [51, 55, 56]. These regimens have been associatedwith decreased early post-transplant morbidity and mortality and have per-mitted allografting in older and medically debilitated patients. However, theimportant clinical question is whether this reduction in toxicity comes at thecost of a loss of anti-tumor activity within the conditioning regimen.

1.2.4 Treatment-Related Toxicities

There are a variety of acute and late toxicities, which can result in significantmorbidity and mortality, that are associated with and specific to allogeneictransplantation [57]. The basic principle underlying the supportive care of thetransplanted patient is prevention. Most transplant complications have a tem-poral relation to the conditioning regimen and the transplant. A simple index,based on pre-transplant comorbidities, has been developed that reliably predictsnon-relapse mortality and survival [58]. This comorbidity index is useful forpatient counseling prior to allogeneic HSCT.

1.2.4.1 Rejection and Graft Failure

The failure to recover hematologic function or the loss of marrow function afterinitial reconstitution constitutes graft failure. Graft rejection occurs whenimmunologically competent cells of host origin destroy the transplanted cellsof donor origin [59]. Graft failure can occur in 5–11% of HLA-identicalrecipients and may be mediated by immunologic graft rejection by the hostimmune system, infections, drugs, or an inadequate stem cell dose. Graft failuregenerally takes place within 60 days of transplantation, though late graft failurehas been known to occur. A number of factors are known to increase the graftfailure rate after allografting, among them, low nucleated cell count infused,T-cell depletion, HLA mismatching, and the use of nonmyeloablative condi-tioning. This complication occurs more commonly in patients who receivetransplants from alternative or HLA-mismatched donors, in T-cell–depletedtransplants, and in patients with aplastic anemiawho receive a non-TBI-containingregimen. Graft rejection is less likely to occur in non-transfused patients withaplastic anemia.

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1.2.4.2 Infections

Due to the utilization of post-transplantation immunosuppressive agents,patients undergoing allogeneic HSCT are at increased risk, particularly tofungal and viral infections, as compared to patients undergoing autologous

stem cell transplantation (reviewed in Chap. 21 byWade and Gea-Banacloche).Infection prophylaxis is routinely employed to guard against bacterial, fungal,and viral pathogens. Fluconazole has been shown to reduce the incidence ofsystemic and superficial fungal infections, but does not affect the incidence of

resistant Candida species; intraconazole has been demonstrated to decreasemold infections [60, 61]. Aspergillosis is the most common cause of death dueto infection after allogeneic HSCT, and the risk of invasive fungal infectionsis increased in patients receiving prolonged, systemic corticosteroid for the

treatment of GvHD. However, newer anti-fungal agents (e.g., voriconazole,caspofungin) have been demonstrated to successfully treat invasive aspergillosisin the transplant setting. Clinical infections with cytomegalovirus (CMV) havebeen significantly reduced utilizing a strategy of monitoring for CMV reactiva-

tion by detection of CMV DNA in leukocytes, plasma, or serum and upondetection, the pre-emptive administration of ganciclovir before overt CMVdisease [62].

1.2.4.3 Genito-Urinary Toxicities

The development of hemorrhagic cystitis is associated with high-dose cyclopho-sphamide within the conditioning regimen. This complication has been largely

abrogated by the use of mesna (sodium 2-sulfanylethanesulfonate) and aggres-sive hydration. Acute renal failure requiring dialysis during the transplantoccurs infrequently [63]. Thrombotic microangiopathy, either idiopathic orassociated with the administration of calcineurin-inhibitors (e.g., cyclosporine)

can be a serious complication after allogeneic HSCT, posing a high mortalityrisk or resulting in end-stage renal disease [64]. Nephrotic syndrome andmembranous nephropathy have been described in long-term survivors; thesecomplications seem to be associated more commonly with chronic GvHD and

nonmyeloablative conditioning [65].

1.2.4.4 Hepatic Toxicities

The most common liver complication associated with transplantation is veno-occlusive disease (VOD)/sinusoidal obstruction syndrome of the liver [66, 67].VOD is caused by endothelial damage in the hepatic sinusoids, and is charac-terized any unexplained weight gain, painful hepatomegaly, and ascites; severe

VOD is associated with a high mortality rate. Beneficial treatments for VODare relatively limited; however, there have been encouraging reports on thetreatment of VOD with defibrotide [68]. The prophylactic use of ursodiol has

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decreased hepatic complications following allogeneic HSCT, especially amongpatients receiving conditioning regimen containing busulfan [69].

1.2.4.5 Acute Graft-Versus-Host Disease

Graft-versus-host disease represents themost important barrier to allogeneicHSCT.Graft-versus-host disease is described as either acute, generally presenting within thefirst 100 days post-transplant (reviewed in Chap. 11 by Antin and Korngold), orchronic, generally presenting after the first 100 days post-transplant (reviewed inChap. 12 byMartin and Pavletic). Risk factors for the development of acute GvHDinclude a female donor (particularly amultiparous donor),more advanced age in thepatient and the donor, and cytomegalovirus sero-positivity of the donor or patientand use of an unrelated donor. Acute GvHD is manifested by symptoms in severalorgan systems, including the skin, gastrointestinal tract, and liver (Table 1.2) [70].The skin manifestations range from a maculopapular rash up to generalized ery-throdermaor desquamation. The severity of liverGvHD is scored on the basis of thebilirubin and the gastrointestinal severity on the quantity of diarrhea per day.Organsmay be involved in isolation or simultaneously. However, delayed de novo presenta-tions of acute GvHD are reported. A clinical grading system (Table 1.2) correlateswith clinical outcome. Severity is described as Grade I (mild) to Grade IV (severe).The incidence of clinically significant GvHD (Grades II–IV) in recipients of HLA-genotypically identical grafts (T cell replete) and using cyclosporine and metho-trexate for GvHD prophylaxis is approximately 40%. Increasing HLA disparityincreases both the incidence and severity of resultant GvHD, with recipients of

Table 1.2 Classification of patients with acute graft-versus-host disease

Clinical staging

Stage Skin Liver Gut

+ Rash<25% BSA Total bilirubin2–3mg/dL

Diarrhea 500–1000mL/day

++ Rash 25–50%BSA

Total bilirubin 3–6mg/dL Diarrhea 1000–1500mL/day

+++ Generalizederythroderma

Total bilirubin 6–15mg/dL Diarrhea>1500mL/day

++++ Desquamationand bullae

Total bilirubin>15mg/dL Pain, with or without ileus

Clinical grading

Stage

Grade Skin Liver Gut PS

0 (none) 0 0 0 0

I + to ++ 0 0 0

II + to +++ + + +

III ++ to +++ ++ to +++ ++ to +++ ++

IV ++ to++++ ++ to ++++ ++ to ++++ +++

BSA¼ body surface area, PS¼ performance status

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phenotypically matched unrelated donor grafts experiencing a 50–80% incidenceof grade II–IV GvHD. Other risk factors for acute GvHD include older age, aparous or alloimmunized donor, less intense immunosuppression, or the use of a Tcell replete versus T cell depleted graft.

Acute GvHD can often be diagnosed on the basis of clinical findings.Histologic confirmation can be valuable in excluding other possibilities suchas infection. Mild GvHD of the skin may demonstrate vacuolar degenerationand infiltration of the basal layer by lymphocytes. With more advanced disease,histologic findings of necrotic dyskeratotic cells with acantholysis may progressto frank epidermolysis. In the liver, early GvHD may be difficult to distinguishfrom hepatitis of other causes.

The best therapy forGvHD is prophylaxis. The prophylactic use of cyclosporineand methotrexate are effective in reducing the incidence of acute GvHD as well asthe survival of transplant patients and is the most commonly used form of GvHDprophylaxis. Cyclosporine is a cyclic polypeptide that prevents T cell activation byinhibiting interleukin-2 (IL-2) production and IL-2 receptor expression. Whileeffective as GvHDprophylaxis, cyclosporine imparts significant toxicities includinghypertension, nephrotoxicity, hypomagnesemia, a risk for seizures, hypertrichosis,gingival hyperplasia, tremors, and anorexia. Tacrolimus is amacolide lactonewhichclosely resembles cyclosporine in mechanism of action, spectrum of toxicities, andpharmacologic interactions. The combination of tacrolimus and methotrexate wasdemonstrated to be superior to cyclosporine and methotrexate in reducing GradeII–IV acute GvHD when used as prophylaxis.

Moderate to severe GvHD (Grades II–IV) requires appropriate treatment. Themainstay of therapy has long been corticosteroid therapy. Treatment for acuteGvHD includes high-dose corticosteroids, anti-thymocyte globulin (ATG), orvarious monoclonal antibodies [71–73]. Methylprednisolone, at a dose of 2 mg/kg/d, can be expected to achieve responses in 40–60% of patients. Higher doses ofsteroids have not been shown to be of greater benefit. Steroid refractory GvHDresponds poorly to second line therapies and is associatedwith increasedmortality.ATG is commonly used as a second line treatment with limited success. Noveltreatments showing efficacy in preliminary studies include extracorporeal photo-therapy and the combination ofmycophenolatemofetil and tacrolimus. In general,acute GvHDof the skin is most responsive to treatment while GvHDof the liver isleast responsive. The fatality rate for acute GvHD may be as high as 50%.

1.2.4.6 Chronic Graft-Versus-Host Disease

Chronic GvHD occurs in 20–50% of long term survivors. Chronic GvHDoccurs most commonly between 100 days and 2 years from the transplant andhas polymorphic features similar to a number of autoimmune diseases [74]. It ismost likely to develop in older patients who also had acute GvHD or receivedperipheral blood rather than bone marrow grafts; in 20% of cases there is nohistory of prior acute GvHD [75]. Adverse prognostic factors include

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thrombocytopenia, a progressive clinical presentation, extensive skin involve-ment, and an elevated bilirubin [76]. Common manifestations include the siccasyndrome, lichen planus-like skin rash, scleroderma-like skin changes, esopha-geal and intestinal fibrosis, obstructive lung disease with or without pneumonitis,and elevated alkaline phosphatase with or without hyperbilirubinemia. Under-lying immunologic deficiencies including hypogammaglobulinemia are common,placing patients at increased risk for infectious events.

Chronic GvHD may be limited or extensive [76]. Limited disease implieslocalized skin involvement with minimal or no liver involvement while extensivedisease suggests generalized skin involvement with or without other organ involve-ment. Patients with limited disease have a good prognosis with 60–70% long-termsurvival while those with extensive disease experience 20–30% long-term survival.Treatment for chronic GvHD is guided by the extent of disease. Initiation oftherapy prior to functional impairment is of critical importance. Treatments forchronic GvHD include corticosteroids, cyclosporine, thalidomide, ultraviolet lighttreatments, or other immunosuppressive agents [77, 78]. Alternatives includeazathioprine, UV light, psoralen-UV-A, extracorporeal photopheresis, and thali-domide. Themost common cause of death in patients with chronicGvHD remainsinfection so all should receive prophylactic antibiotics with or without intravenousimmunoglobulin [78].

1.2.4.7 Late Complications

These include endocrine toxicities such as hypothyroidism, hypogonadism, orgrowth hormone deficiency in younger patients; pulmonary effects may includeobstructive lung disease or pulmonary fibrosis; and other late effects includingcataracts and leukoencephalopathy [57].

1.3 Current Indications for Allogeneic Hematopoietic Stem Cell

Transplantation for Patients with Malignancy

There is clinical evidence that allogeneic HSCT can provide benefit, defined as free-domof progression or overall survival, formost hematologicmalignancies.However,the beneficial effects of allogeneic HSCT vary greatly with each type of malignancy.Data indicate that due to their relative responsiveness to cytotoxic therapy, myeloa-blative conditioning regimens with allogeneic HSCT result in higher response ratesthan cytotoxic or conventional agents for almost all hematologic malignancies.However, the durability of these responses and their effect on survival varies fromdisease todisease. Similarly, there is evidenceof a clinicalGvT effect in almost everyhematologic disease; however, its potency and clinical relevance are highlyvariable. Interpretation of the results of trials of HSCT always is complicatedby issues of patient selection. This can lead to either underestimating theefficacy of allogeneic HSCT if it is used after exhausting all other available

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therapies or overestimating its efficacy if only the patients with favorableprognostic characteristics are selected. The specific indications for allogeneicHSCT are covered in the chapters for each respective disease. This sectionbriefly addresses the outcomes for malignancies with allogeneic HSCT.

1.3.1 Acute Myeloid Leukemia

With the exception of acute promyelocytic leukemia there is no doubt thatallogeneic HSCT offers the highest anti-leukemic activity after a conventionalinduction and intensification therapy for acute myeloid leukemia (AML; a.k.a.acute myelogenous leukemia) patients in first remission. Randomized con-trolled trials comparing autologous and allogeneic HSCT to conventionalchemotherapy in patients with AML in first complete remission have demon-strated improved leukemia-free survival with both forms of HSCT; however,there has been no significant improvement in overall survival due to increasedtreatment related mortality with allogeneic HSCT [79, 80]. The one exceptionhas been in pediatric AML, where allogeneic HSCT has been demonstrated toimprove both leukemia-free and overall survival for patients transplanted infirst complete remission [81]. For AML patients with poor prognostic features(adverse cytogenetics, secondary leukemias, presence of minimal residual dis-ease) there are strong indications for allogeneic HSCT in first complete remis-sion (CR1) [82]. The outcome of HSCT for patients beyond CR1 is worse whencompared to the use of transplant while in CR1, but for these patients allograft-ing still remains the most effective strategy to obtain long-term disease control.Reduced-intensity and nonmyeloablative conditioning regimens may increasethe applicability of allogeneic HSCT for older AML patients [83].

1.3.2 Acute Lymphoblastic Leukemia

For adult patients with poor-risk acute lymphoblastic leukemia (ALL), mostinvestigators recommend an allogeneic transplant [84–86]. The results forpatients in later remissions, early relapse, or primary refractory disease areclearly inferior to those of patients inCR1, but in nearly all of these circumstancesif an HLA donor is available, an allogeneic HSCT is associated with improvedoutcomes when compared to prior therapy [87].

1.3.3 Chronic Myeloid Leukemia

Before the development of imatinib mesytale chronic myeloid leukemia (CML;a.k.a. chronic myelogenous leukemia) was one of the major indications for

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allogeneic HSCT, and a well established curative strategy for CML with5-year disease-free survival rates of 85% [88]. After the advent of imatiniband the new tyrosine kinase inhibitors (TKI), allogeneic transplantation is nolonger the first option for CML patients [89]. Use of allogeneic HSCT islimited to those patients in chronic phase who failed one, or in some instances,two lines of TKI [90]. The GvT effect is critical in the potential cure of CMLwith allogeneic transplantation, thus nonmyeloablative and reduced-intensityconditioning regimens in this group of patients would seem an attractivestrategy. However it is not yet possible to conclude that for younger patients,those younger than 40–50 years, either nonmyeloablative or reduced-intensityallogeneic HSCT offers a major advantage to patients who would otherwise becandidates for an allografting with conventional, myeloablative conditioning[90]. Patients with accelerated, blastic or second chronic phase CML can notbe cured with imatinib or the new TKI dasatinib, and responses are usually ofshort duration. Although clinical results of allogeneic HSCT are poor forthese advanced phases of CML, it continues to be the only potential curativeapproach [91].

1.3.4 Myelodysplastic Syndromes

Allogeneic HSCT is the only curative treatment for myelodysplastic syndromes(MDS). Because of the older age of patients with MDS, transplantation hasgenerally been reserved for patients with higher riskMDS orMDS transformingto AML. The best results have been obtained in relatively younger patients, whoare earlier in their disease course and have not received any prior therapy. Toidentify factors influencing transplantation outcome for MDS, the InternationalBone Marrow Transplantation Registry (IBMTR) studied 452 recipients ofHLA-identical sibling transplants for MDS [92]. Three-year transplantation-related mortality, relapse, disease-free survival, and overall survival rates were37%, 23%, 40%, and 42%, respectively. Multivariate analyses showed thatyoung age and platelet counts higher than 100,000 at transplantation wereassociated with lower transplant-related mortality and higher disease-free andoverall survival rates. Because the optimal timing for transplantation forMDS isunknown, the IBMTR constructed aMarkov model to examine three transplan-tation strategies for newly diagnosed MDS: transplantation at diagnosis, trans-plantation at leukemic progression, and transplantation at an interval fromdiagnosis but prior to leukemic progression [93]. Analyses using individualpatient risk-assessment data from transplantation and non-transplantation regis-tries were performed using the International Prognostic Scoring System (IPSS)for MDS with adjustments for quality of life. For low and intermediate-1 IPSSgroups, delayed transplantation maximized overall survival. Transplantationprior to leukemic transformation was associated with a greater number of life

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years than transplantation at the time of leukemic progression. In a cohort of

patients under the age of 40 years, an even more marked survival advantage

for delayed transplantation was noted. For intermediate-2 and high IPSS

groups, transplantation at diagnosis maximized overall survival. There is

evidence that reduced-intensity allogeneic HSCT may benefit older patients

with MDS [94, 95].

1.3.5 Non-Hodgkin Lymphoma and Hodgkin Lymphoma

Although allogeneic HSCT has been reported to yield long-term disease-free

survival for patients with intermediate and high-grade non-Hodgkin‘s lympho-

mas (NHL), the demonstration of a potent GvT effect against NHL is less clear,

and the efficacy of donor lymphocyte infusion in lymphoma is anecdotal at best

[96–99]. Consequently, the specific role of allogeneic HSCT has not been defined.

There are data that nonmyeloablative and reduced-intensity allogeneic HSCT

may provide benefits for patients with recurrent follicular NHL; however, the

data indicate that this approach requires that the disease remains chemotherapy-

sensitive [98].Allogeneic HSCT has had a limited role in the treatment of Hodgkin lym-

phoma (HL; a.k.a. Hodgkin‘s disease) due to the efficacy of autologous HSCT,

the treatment-related toxicities associated withmyeloablative allogeneic HSCT,

and a relative lack of evidence of aGvT effect against HL. However, recent data

indicate that reduced-intensity allogeneic HSCT may benefit patients with

recurrent HL, and a GvT effect against HD may exist [100].

1.3.6 Multiple Myeloma

A graft-versus-myeloma effect has been demonstrated, but the use of allo-

geneic HSCT for multiple myeloma had been limited since transplant-

related mortality in this group of patients with conventional myeloablative

regimens was very high, 30–50% [101]. Data with nonmyeloablative regi-

mens are encouraging, and based on the high transplant-related mortality,

multiple myeloma was a good model for investigating the feasibility of

nonmyeloablative transplants in this type of patients. Although several

studies have demonstrated that transplant-related mortality was decreased

with nonmyeloablative conditioning regimens, the relapse rate is greater

when compared to standard allografting [90]. Results of a prospective

biologically assigned study suggest, however, that the use of nonmyeloa-

blative allogeneic HSCT may be superior to autologous HSCT in newly

diagnosed myeloma patients [102].

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1.3.7 Solid Tumors

There has been considerable interest in investigating the presence of a GvTeffect in a variety of solid tumors, including renal cell carcinoma and breastcancer [103–105]. Childs and colleagues reported on a series of 19 patients withmetastatic renal cell carcinoma who underwent nonmyeloablative allogeneicstem cell transplantation [103]. Nine patients had responsive disease (47%), ofwhich three were complete responses.

1.4 Conclusion

There has been tremendous success since the 1980s in the increased safety ofallogeneic HSCT and in the expanding application of this treatment to morepatient populations. Areas currently under development that may further improvethe use and efficacy of transplantation include continuous improvements in sup-portive care for transplant patients, broadened use of alternative donors, morerefined graft manipulations, and further improvements in the nonmyeloablativetransplantation techniques and GvHD prevention. Future progress depends onour ability to identify safer and better-targeted anti-tumor therapies that can beincorporated in the transplantation regimens without attenuating the GvTresponses. This remains a challenge for future clinical research.

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