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Allogeneic Stem Cell Transplantation Current Clinical
Oncology 1st Edition Laughlin Digital Instant Download
Author(s): Laughlin, Mary J. (ed.)
ISBN(s): 9780896039797, 089603979X
Edition: 1
File Details: PDF, 3.03 MB
Year: 2002
Language: english
Allogeneic
Stem Cell
Transplantation
Clinical Research and Practice
Edited by
Mary J. Laughlin, MD
Hillard M. Lazarus, MD
HUMANA PRESS
Contents i
ALLOGENEIC STEM CELL TRANSPLANTATION

ii Contents
CURRENT CLINICAL ONCOLOGY

Maurie Markman, MD, SERIES EDITOR
Treatment of Acute Leukemias: New Directions for Clinical Research, edited by

CHING-HON PUI, 2003
Allogeneic Stem Cell Transplantation: Clinical Research and Practice, edited by MARY J.
LAUGHLIN AND HILLARD M. LAZARUS, 2003
Chronic Leukemias and Lymphomas: Clinical Management, edited by GARY J. SCHILLER,
2003
Colorectal Cancer: Multimodality Management, edited by LEONARD SALTZ, 2002
Breast Cancer: A Guide to Detection and Multidisciplinary Therapy, edited by MICHAEL H.
TOROSIAN, 2002
Melanoma: Biologically Targeted Therapeutics, edited by ERNEST C. BORDEN, 2002
Cancer of the Lung: From Molecular Biology to Treatment Guidelines, edited by ALAN B.
WEITBERG, 2001
Renal Cell Carcinoma: Molecular Biology, Immunology, and Clinical
Management, edited by RONALD M. BUKOWSKI AND ANDREW NOVICK, 2000
Current Controversies in Bone Marrow Transplantation, edited by BRIAN J. BOLWELL,
2000
Regional Chemotherapy: Clinical Research and Practice, edited by MAURIE MARKMAN,
2000
Intraoperative Irradiation: Techniques and Results, edited by L. L. GUNDERSON, C. G.
WILLETT, L. B. HARRISON, AND F. A. CALVO, 1999
Contents iii
ALLOGENEIC
STEM CELL
TRANSPLANTATION
Clinical Research and Practice
Edited by
MARY J. LAUGHLIN, MD
Ireland Cancer Center,
Case Western Reserve University, Cleveland, OH
and
HILLARD M. LAZARUS, MD
Ireland Cancer Center,
Case Western Reserve University, Cleveland, OH
HUMANA PRESS
TOTOWA, NEW JERSEY
iv Contents
© 2003 Humana Press Inc.

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Library of Congress Cataloging-in-Publication Data
Allogeneic stem cell transplantation : clinical research and practice / edited by Mary J. Laughlin and Hillard M. Lazarus
p. ; cm. -- (Current clinical oncology)
Includes bibliographical references and index.
ISBN 0-89603-979-X (alk. paper); 1-59259-333-X (e-book)
1. Blood--Diseases. 2. Hematopoietic stem cells--Transplantation. I. Laughlin, Mary J. II. Lazarus, Hillard M. III.
Current clinical oncology (Totowa N.J.)
[DNLM: 1. Hematopoietic Stem Cell Transplantation. 2. Transplantation, Homologous--methods. WH 380 A441
2003]
RC636 .A45 2003
617.4'4--dc21
200268939
PREFACE
Contents v
Hematopoietic stem cell transplantation for patients with hematologic disorders is under-
going fast-paced changes, owing to evolving paradigms of stem cell plasticity and improved
understanding of mechanisms underlying immunologic tolerance. In Allogeneic Stem Cell
Transplantation, the editors have focused on assigning topics relevant to evolving knowledge
in the field in order to guide clinicians in decision-making and management of their patients.
The leaders in this discipline have responded by providing state-of-the-art discussions
addressing these topics.
Important advances in patient management include the use of tyrosine kinase inhibitors in
the treatment of chronic myelogenous leukemia that has abruptly changed previous standard
care paths for these patients in tracking toward allografting as consolidative therapy. More-
over, the results of randomized trials in breast cancer over the past few years have guided
clinicians away from use of autologous transplantation to focus now on newer perspectives
of potential graft-vs-tumor effects after allogeneic transplantation. The administration of
nonmyeloablative conditioning has also brought forth new concepts in the management of
hematologic malignancies, thought to be of particular importance in patients with multiple
myeloma and low grade non-Hodgkin’s lymphomas. The reduced toxicity of these novel
conditioning regimens has also raised new possibilities in the application of allogeneic stem
cell transplantation for patients with non-malignant hematologic disorders and selected solid
tumors such as renal cell carcinoma.
Further examples of innovation in allogeneic transplantation outlined in this text include
the results of phase I trials of umbilical cord blood as a new stem cell source, confirming its
safety and thereby alleviating previous restrictions for patients for whom an HLA-matched
graft from an adult donor is not available. The previous focus of stem cell transplant physicians
on measurement and characterization of CD34-expressing hematopoietic stem cells has broad-
ened recently to examine the role of marrow mesenchymal stem cells and graft accessory cells
in facilitating engraftment and immune reconstitution. These issues of graft engineering play
an important role as the field has transitioned from the routine use of bone marrow to mobilized
peripheral blood stem cell grafting. Finally, the ongoing attempts to discern lymphocyte
populations critical in mediating graft-vs-leukemia/lymphoma effects and immune tolerance
are anticipated to benefit clinicians and patients, as well to reduce graft-vs-host disease inci-
dence and severity while preserving antitumor effects in patients undergoing allogeneic trans-
plantation.
The editors hope that this new information, well-summarized by the authors in Allogeneic
Stem Cell Transplantation, will prove of significant benefit to clinicians in the approach to and
care of their patients.
Mary J. Laughlin, MD
Hillard M. Lazarus, MD
v
vi Contents
CONTENTS
Contents vii
Preface .....................................................................................................................................v
Contributors ........................................................................................................................... ix
PART I. HISTORICAL PERSPECTIVE
1 Hematopoietic Stem Cell Transplantation:
A Historical Perspective ........................................................................................... 3
Frederick R. Appelbaum
PART II. DISEASE INDICATIONS: ALLOGENEIC TRANSPLANTATION
2 Allogeneic Hematopoietic Cell Transplantation for Adult Patients
with Acute Myelogenous Leukemia ....................................................................... 13
Henry C. Fung and Stephen J. Forman
3 Allogeneic Stem Cell Transplantation for Adult Acute
Lymphoblastic Leukemia ....................................................................................... 29
Partow Kebriaei and Wendy Stock
4 Chronic Myelogenous Leukemia ................................................................................ 47
Edward Copelan
5 Allogeneic Stem Cell Transplantation for Breast Cancer .......................................... 57
Abby B. Siegel and Linda T. Vahdat
6 Allogeneic Transplantation for the Treatment of Multiple Myeloma ....................... 69
Stefano Tarantolo and Philip J. Bierman
7 Non-Hodgkin's Lymphoma ......................................................................................... 83
Igor Espinoza-Delgado and Dan L. Longo
PART III. ALLOGENEIC GRAFT SELECTION
8 Blood vs Marrow Allogeneic Stem Cell Transplantation ........................................ 103
Daniel Anderson and Daniel Weisdorf
9 Haploidentical Stem Cell Transplantation ................................................................ 117
Hillard M. Lazarus and Jacob M. Rowe
10 Umbilical Cord Blood Transplantation .................................................................... 129
Juliet Barker and John E. Wagner
11 Mesenchymal Stem Cells in Allogeneic Transplantation ........................................ 151
Omer N. Koç and Stanton L. Gerson
12 Cytokines in Allogeneic Stem Cell Mobilization..................................................... 159
Ravi Vij, Randy Brown, and John F. DiPersio
13 Nonmyeloablative Allogeneic Transplantation ........................................................ 169
David A. Rizzieri and Nelson J. Chao
PART IV. SUPPORTIVE CARE IN ALLOGENEIC TRANSPLANTATION
14 Recent Developments in Epidemiology and Management
of Invasive Fungal Infections ............................................................................... 191
Andreas H. Groll and Thomas J. Walsh
vii
viii Contents
15 Immune Recovery Following Allogeneic Blood Transplantation:

Mechanisms of Immune Dysfunction .................................................................... 215
James E. Talmadge
16 Grading and Management of Graft-vs-Host Disease ............................................... 237
Donna Przepiorka
17 Posttransplant EBV-Associated Disease .................................................................. 261
Thomas G. Gross and Brett J. Loechelt
PART V. PREVENTION AND MANAGEMENT OF RELAPSE
AFTER ALLOGENEIC TRANSPLANTATION
18 Allogeneic Antitumor Vaccine Strategies ................................................................ 273
Ginna G. Laport and Carl H. June
19 Donor Leukocyte Infusions ....................................................................................... 287
Robert H. Collins, Jr.
20 Second Hematopoietic Stem Cell Transplantation
for the Treatment of Graft Failure, Graft Rejection, or Relapse ......................... 311
Steven N. Wolff
PART VI. PRECLINICAL STUDIES IN ALLOGENEIC TRANSPLANTATION
21 The Role of T Cell Depletion in Bone Marrow Transplantation ............................. 327
Yair Reisner and Massimo F. Martelli
22 Minimal Residual Disease in Allogeneic Recipients ............................................... 343
Jerald P. Radich
23 Nonhuman Primate Models of Hematopoietic Stem Cell Transplantation ............. 355
Steven M. Devine and Ronald Hoffman
24 In Vivo Models for the Study of Graft-vs-Host Disease
and Graft-vs-Tumor Effects .................................................................................. 373
Kai Sun, William J. Murphy, and Lisbeth A. Welniak
25 Allogeneic Effector Cell Populations:
Separating GVL from GVHD................................................................................ 387
Michael R. Verneris and Robert S. Negrin
26 Dendritic Cells:
Immunobiology and Potential Use for Cancer Immunotherapy.......................... 411
David Avigan
PART VII. EPILOGUE
27 Epilogue ..................................................................................................................... 441
James R. Mason and Ernest Beutler
Index ................................................................................................................................... 445
CONTRIBUTORS
Contents ix
DANIEL ANDERSON, MD, Adult Blood and Marrow Transplant Program, Department
of Medicine, University of Minnesota, Minneapolis, MN
FREDERICK R. APPELBAUM, MD, Clinical Research Division, Fred Hutchinson Cancer
Research Center, Seattle, WA
DAVID AVIGAN, MD, Bone Marrow Transplantation, Beth Israel-Deaconess Medical
Center, Boston, MA
JULIET BARKER, MBBS (HONS), Blood and Marrow Transplant Program, Department of
Medicine, University of Minnesota, MN
ERNEST BEUTLER, MD, Molecular and Experimental Medicine, The Scripps Research
Institute, La Jolla, CA
PHILIP J. BIERMAN, MD, Oncology/Hematology, University of Nebraska Medical Center,
Omaha, NE
RANDY BROWN, MD, Section of Bone Marrow Transplant and Leukemia, Division of
Medical Oncology, Washington University School of Medicine, St. Louis, MO
NELSON J. CHAO, MD, Division of Oncology and Bone Marrow Transplantation, Duke
University Medical Center, Durham, NC
ROBERT H. COLLINS, JR., MD, Bone Marrow Transplantation Program, University of Texas
Southwestern Medical Center at Dallas, Dallas, TX
EDWARD COPELAN, MD, BMT Program, The Ohio State University Hospital, Columbus, OH
STEVEN M. DEVINE, MD, Section of Bone Marrow Transplantation and Leukemia, Division
of Medical Oncology, Washington University School of Medicine, St. Louis, MO
JOHN F. DIPERSIO, MD, PhD, Section of Bone Marrow Transplantation and Leukemia,
Division of Medical Oncology, Washington University School of Medicine,
St. Louis, MO
IGOR ESPINOZA-DELGADO, MD, National Institute on Aging, National Institutes of Health,
Baltimore, MD
STEPHEN J. FORMAN, MD, Division of Hematology and Bone Marrow Transplantation, City
of Hope National Medical Center, Duarte, CA
HENRY C. FUNG, MD, Division of Hematology and Bone Marrow Transplantation, City of
Hope National Medical Center, Duarte, CA
STANTON L. GERSON, MD, Ireland Cancer Center, University Hospitals of Cleveland, Case
Western Reserve University, Cleveland, OH
ANDREAS H. GROLL, MD, Center for Bone Marrow Transplantation, Wilhelms-University
Medical Center, Muenster, Germany
THOMAS G. GROSS, MD, PhD, BMT Program, Department of Medicine, Children's Hospital
Medical Center, Cincinnati, OH
RONALD HOFFMAN, MD, Chief, Section of Hematology and Oncology, and Director, UIC
Cancer Center, College of Medicine, University of Illinois at Chicago, Chicago, IL
CARL H. JUNE, Abramson Family Cancer Research Institute and the Department of Pathology
and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
PARTOW KEBRIAEI, MD, Section of Hematology/Oncology, Department of Medicine,
University of Chicago Medical Center, Chicago, IL
OMER N. KOÇ, MD, Ireland Cancer Center, University Hospitals of Cleveland, Case
Western Reserve University, Cleveland, OH
ix
xx Contributors
Contents
GINNA G. LAPORT, Division of Bone Marrow Transplantation, Stanford University Medical

Center, Stanford, CA
MARY J. LAUGHLIN, MD, Allogeneic Transplant Program, Ireland Cancer Center, University
Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH
HILLARD M. LAZARUS, MD, Blood and Marrow Transplant Program, Ireland Cancer Center,
University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH
BRETT J. LOECHELT, MD, Division of Hematology/Oncology, Children's Hospital Medical
Center, Cincinnati, OH
DAN L. LONGO, MD, National Institute on Aging, National Institutes of Health, Baltimore, MD
MASSIMO F. MARTELLI, MD, PhD, Chair of Hematology, University of Perugia, Perugia, Italy
JAMES R. MASON, MD, Blood and Marrow Transplantation Program, Scripps Clinic,
La Jolla, CA
WILLIAM J. MURPHY, PhD, Department of Microbiology, University of Nevada Reno, Reno, NV
ROBERT S. NEGRIN, MD, Bone Marrow Transplantation, Stanford University School
of Medicine, Stanford, CA
DONNA PRZEPIORKA, MD, PhD, Malignant Hematology and Transplantation, University of
Tennessee, Memphis, TN
JERALD P. RADICH, MD, Clinical Research Division, Fred Hutchinson Cancer Research
Center, Seattle, WA
YAIR REISNER, PhD, Immunology, Weizmann Institute of Science, Rehovot, Israel
DAVID A. RIZZIERI, MD, Department of Medicine, Duke University Medical Center, Durham, NC
JACOB M. ROWE, MD, Department of Hematology, Rambam Medical Center, Technion,
Haifa, Israel
ABBY B. SIEGEL, MD, Division of Medical Oncology, Department of Medicine, Herbert Irving
Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons,
New York, NY
WENDY STOCK, MD, Section of Hematology/Oncology, Department of Medicine, University
of Chicago Medical Center, Chicago, IL
KAI SUN, MD, PhD, Department of Microbiology, University of Nevada Reno, Reno, NV
JAMES E. TALMADGE, PhD, Departments of Pathology and Microbiology, University
of Nebraska Medical Center, Omaha, NE
STEFANO TARANTOLO, MD, Oncology/Hematology, University of Nebraska Medical Center,
Omaha, NE
LINDA T. VAHDAT, MD, Medical Oncology Department, Milstein Hospital, Columbia
University, New York, NY
MICHAEL R. VERNERIS, MD, Division of Pediatric Hematology, Oncology, and Bone Marrow
Transplantation, Stanford University, Stanford, CA
RAVI VIJ, MD, Section of Bone Marrow Transplantation and Leukemia, Division of Medical
Oncology, Washington University School of Medicine, St. Louis, MO
JOHN E. WAGNER, MD, Department of Pediatrics, Blood and Marrow Transplant Program
of the University of Minnesota School of Medicine, Minneapolis, MN
THOMAS J. WALSH, Immunocompromised Host Section, Pediatric Oncology Branch,
National Cancer Institute, National Institutes of Health, Bethesda, MD
DANIEL WEISDORF, MD, Adult Blood and Marrow Transplant Program, Department
of Medicine, University of Minnesota, Minneapolis, MN
LISBETH A. WELNIAK, PhD, Department of Microbiology, University of Nevada Reno, Reno, NV
STEVEN N. WOLFF, MD, Stem Cell Transplantation Program, Department of Medicine,
Vanderbilt University, Nashville, TN, and Aastrom Biosciences, Ann Arbor, MI
Chapter 1 / Hematopoietic Stem Cell Transplantation 1
I HISTORICAL PERSPECTIVE
2 Part I / Historical Perspective
1 Hematopoietic Stem Cell Transplantation

A Historical Perspective
Frederick R. Appelbaum, MD
CONTENTS
INTRODUCTION
EARLY STUDIES LEADING TO THE FIRST HUMAN TRIALS
INITIAL TRIALS IN HUMANS
LABORATORY STUDIES LEADING TO THE FIRST SUCCESSES IN PATIENTS
INITIAL SUCCESSES IN HUMAN MARROW TRANSPLANTATION
SUBSEQUENT ADVANCES IN THE APPLICATION OF HEMATOPOIETIC CELL
TRANSPLANTATION
A TRIBUTE TO E. DONNALL THOMAS
REFERENCES
1. INTRODUCTION
Over the last half-century, hematopoietic cell transplantation has evolved from an idea to
a well-established therapy used in the treatment of tens of thousands of individuals annually.
This evolution is the product of laboratory-based investigations, studies using animal models,
and especially clinical trials involving human subjects. The following brief account highlights
some of the more outstanding contributions, with particular emphasis on those made during the
earlier development of the procedure (Table 1). In this brief recounting it is possible to include only
a small fraction of the valuable contributions, and apologies are prospectively offered to all of those
whose important work is not mentioned. For a more complete retelling of the story, with more
extensive bibliographies, the reader is referred to a number of other excellent papers (1–4).
2. EARLY STUDIES LEADING TO THE FIRST HUMAN TRIALS

While earlier references to oral or intravenous administration of bone marrow exist, the
story of hematopoietic cell transplantation really begins shortly after World War II and the first
(and only) use of nuclear weapons. The realization that bone marrow failure was a predictable
and fatal consequence of exposure to relatively low levels of radiation spurred considerable
interest in the biology of radiation exposure. A landmark study was published in 1949 by
Jacobson et al., who showed that mice exposed to an otherwise lethal dose of radiation would
survive if their spleens were protected by lead foil (5). Lorenz et al. showed that this protective
From: Current Clinical Oncology: Allogeneic Stem Cell Transplantation

Edited by: Mary S. Laughlin and Hillard M. Lazarus © Humana Press Inc., Totowa, NJ
3
Table 1
Milestones in the Development of Hematopoietic Cell Transplantation
1949 Spleen shielding experiment of Jacobson.
1957 First human twin transplants for leukemia.
1962 Successful allogeneic transplants in dogs.
1968 First successful allogeneic transplants in humans.
1977 Successful application of autologous marrow transplantation.
1990 Dr. Thomas awarded Nobel Prize.
effect could be transferred between animals when they demonstrated that infusion of marrow
or spleen cells from a healthy animal to an irradiated one reversed the otherwise lethal effects
of radiation (6). At the time, it was unclear whether this protective effect was due to humoral
factors produced by the nonirradiated cells or due to the cells themselves. Two experiments
proved the cellular nature of radiation protection. Main and Prehn in 1955 reported that radi-
ated mice given marrow grafts from nonsyngeneic donors not only recovered, but could no
longer reject donor skin grafts. This demonstration of active tolerance strongly implied that the
radiation protection effect was not simply the result of a humoral factor stimulating recovery
of host hematopoiesis (7). The following year, Ford et al. provided definitive evidence of the
cellular nature of radiation protection when they used cytogenetic markers to demonstrate the
donor identity of marrow in irradiated hosts post-transplant (8). Finally, in 1956, Barnes et al.
published their classic paper describing the use of supralethal radiation followed by marrow
grafting as treatment for murine leukemia (9). In these studies, they noted eradication of
leukemia in irradiated mice receiving allogeneic marrow, but not syngeneic marrow, thus
demonstrating for the first time the possibility of a graft-vs-leukemia effect.
3. INITIAL TRIALS IN HUMANS

The demonstration that systemic irradiation could eradicate a normal marrow and that
marrow function could be restored by infusion of syngeneic marrow, at least in mice, led
Thomas et al. to attempt a similar approach in humans (10). In 1957, he reported the results of
treating two patients suffering from advanced leukemia using supralethal radiation followed
by an infusion of marrow from their identical twins (11). Both patients engrafted promptly,
demonstrating the feasibility of the approach, but subsequently their leukemia recurred. Fur-
ther attempts at marrow transplants using donors other than identical twins were made over the
next decade. The first patient engrafted using allogeneic marrow was reported by Mathe in
1965, but the patient died of complications probably related to graft-vs-host disease (12). In
1970, Bortin et al. published a report summarizing the results of approx 200 allogeneic trans-
plants performed during the 1950s and 1960s and concluded that none had resulted in long-
term survival (13). The problems that limited the success of transplantation during this era were
the limited understanding of details of human histocompatibility, lack of experience with the
use of immunosuppressive drugs, and shortcomings in supportive care techniques.
4. LABORATORY STUDIES LEADING TO THE FIRST SUCCESSES IN PATIENTS

A number of critical laboratory studies were performed during the 1950s and 1960s, which
led to the first successful allogeneic transplants in humans. In the late 1950s, Dausset (14) and
van Rood et al. (15) described a number of antigens expressed on human leukocytes (human
leukocyte antigens or HLA) that influenced the success of skin grafts and, thus, were thought
to be generally involved in histocompatibility. The ability to select HLA-compatible siblings

as marrow donors was one of the major advances leading to the ultimate success of allogeneic
transplantation in humans. A series of experiments conducted in dogs defined many additional
principles necessary for the ultimate success of transplantation in humans. Dogs, unlike mice,
are an outbred species, and the relative importance of histocompatibility or incompatibility
turns out to reasonably parallel their importance in humans. Studies in dogs, conducted prima-
rily by Thomas and his colleagues, demonstrated the dose of radiation necessary to achieve
engraftment, the requirement for histocompatibility matching to prevent graft rejection or
lethal graft-versus-host disease, and the ability of postgrafting methotrexate to adequately
suppress acute graft-vs-host disease to allow for the majority of animals to become long-term
healthy survivors after receiving marrow grafts from histocompatible donors (16–19). The
increased understanding of human histocompatibility, coupled with advances in the tech-
niques of transplantation and improvements in supportive care, set the stage for the first
successes in human marrow transplantation.
5. INITIAL SUCCESSES IN HUMAN MARROW TRANSPLANTATION

The first therapeutically successful human marrow transplants were reported in 1968 and
1969, when three infants with severe combined immunodeficiency disease were successfully
transplanted from their HLA-matched siblings (20–22). According to recent reports, these
patients continue to survive more than three decades after transplantation. Transplantation for
severe combined immunodeficiency from HLA-identical siblings does not require a prepara-
tive regimen to prevent graft rejection or eliminate disease. The first successful transplants
requiring a preparative regimen were reported three years later, in 1972, when the Seattle group
reported success in transplanting patients for aplastic anemia from HLA-identical siblings
using a preparative regimen of high-dose cyclophosphamide and posttransplant methotrex-
ate (23). At approximately the same time, the first successful transplants for acute leukemia
were being performed. In 1975, Thomas et al. published a review article describing the state
of the art at that time, and noting that successful engraftment could be achieved in most patients
with aplastic anemia and acute leukemia and that some of these patients appeared to be surviv-
ing without evidence of their disease for at least several years posttransplant (24). Two years
later the same group published a follow-up of the first 100 patients transplanted for advanced
leukemia and provided convincing evidence that transplantation could, in fact, cure at least a
portion of such patients (25).
Over the next several years, a number of other notable hematopoietic cell transplant “firsts”
were reported. These firsts involved the use of alternate sources of stem cells, the use of
transplantation to treat additional diseases, and the use of transplantation earlier in the disease
course. Prior to 1977, there had been several attempts to use autologous marrow to support the
administration of high-dose curative therapy. While these reports suggested that autologous
transplants might lead to engraftment, lack of genetic markers or control groups prohibited
definitive conclusions, and the clinical situations studied were so advanced that no clinical
benefit was obvious (26,27). In 1977, the group at the National Institute of Health (NIH)
published a controlled trial demonstrating that previously cryopreserved autologous marrow
was capable of establishing hematopoietic function in humans (28). These same studies dem-
onstrated that the high-dose therapy made possible by transplantation could cure selected
patients of recurrent non-Hodgkin’s lymphoma (29).
The demonstration that transplantation could be effective therapy for patients with endstage
disease led a number of investigators to study the role of transplantation earlier in the disease
course. In 1979, the first reports emerged showing encouraging results in patients with acute
myeloid leukemia transplanted in first remission (30,31) and for patients with chronic myeloid
leukemia transplanted while in chronic phase (32). Several years later, the first successful
transplants for patients with hemoglobinopathies, including β-thalassemia and sickle cell
anemia, were reported (33,34). It was also during the early 1980s that the first reports of
successful transplants using marrow from HLA-matched unrelated donors began to emerge.
6. SUBSEQUENT ADVANCES IN THE APPLICATION

OF HEMATOPOIETIC CELL TRANSPLANTATION
Since the early 1980s, there have been a large number of notable advances, a few of which
are mentioned here. These advances, and many others that are not discussed here for lack of
space, have substantially improved the outcome of hematopoietic cell transplantation and are
the subject of this textbook.
6.1. Source of Stem Cells

The use of growth-factor-mobilized hematopoietic stem cells harvested from peripheral
blood was shown to dramatically hasten engraftment and has replaced marrow as the preferred
source of stem cells for autologous, and in some cases allogeneic, engraftment (35,36). Placen-
tal cord blood has become a useful source of stem cells, especially for pediatric patients (37).
Large donor registries have been created, making matched unrelated donor transplantation
available for the majority of patients (38,39). Advances in HLA-typing technology have
allowed for continued improvements in selection of appropriate donors (40).
6.2. Preparative Regimens

Preparative regimens based on busulfan and cyclophosphamide were developed and have
become the most frequently used for treating myeloid malignancies (41). The development of
nonablative preparative regimens provides a method for capturing a graft-vs-tumor effect
without exposing patients to the toxicities of high-dose therapy (42–44). The demonstration
that infusion of viable donor lymphocytes can result in complete disappearance of leukemia
after posttransplant recurrence, not only provides physicians with another therapeutic tool, but
has generally fueled efforts in the field of clinical tumor immunology (45).
6.3. Graft-vs-Host Disease

The combination of methotrexate plus cyclosporin was shown to provide better prophylaxis
of acute graft-vs-host disease than either agent alone and became the standard of care (46,47).
Techniques involving the removal of T-cells from the stem cell inoculum were shown to offer
an alterative method to prevent graft-vs-host disease (48,49).
6.4. Supportive Care Techniques

The use of hematopoietic growth factors was shown to accelerate hematopoietic recovery after
autologous stem cell transplantation (50). Methods to prevent cytomegalovirus (CMV) disease,
by the use of CMV seronegative blood products in CMV seronegative patients or by the use of
ganciclovir, dramatically reduced the death rate from CMV (51,52). The prophylactic use of
fluconazole likewise improved overall survival following allogeneic transplantation (53).
The advances noted above, as well as many others, have led to the widespread application
of hematopoietic cell transplantation as an effective treatment for selected patients with essen-
tially all hematologic diseases, both malignant and nonmalignant. Important experiments are
underway determining whether approaches requiring hematopoietic cell transplantation have
a role in the treatment of autoimmune disorders and nonhematopoietic malignancies.
Fig. 1. Dr. E. Donnall Thomas, recipient of the 1990 Nobel Prize for Physiology and Medicine (along
with Dr. Joseph Murray), recognizing the field of organ transplantation.
7. A TRIBUTE TO E. DONNALL THOMAS

While many individuals, including Robert Good, George Santos, and Rainer Storb, have
made enormous contributions to the field of hematopoietic cell transplantation, the role of E.
Donnall Thomas stands out (Fig. 1). In the mid-1950s, Thomas became aware of the studies
of Leon Jacobson and others and became convinced of the clinical potential of marrow trans-
plantation. In 1955, Thomas moved to the Mary Imogene Bassett Hospital in Cooperstown,
New York, where he began working with Dr. Joe Ferrebee on marrow transplantation, both in
dogs and in humans. It was there that Thomas published the first report of successful transplan-
tation in identical twins, but became aware of failures of the procedure in the nontwin setting.
Thomas moved to the University of Washington in Seattle in 1963, and there he and his
colleagues developed techniques for histocompatibility typing in dogs and demonstrated that
by selecting matched donors and using posttransplant methotrexate, it was possible to success-
fully transplant marrow between matched litter mates in virtually every case. These experi-
ments set the stage for renewed attempts to apply transplantation to the treatment of human
disease. In the late 1960s, Thomas wrote a program project grant that was funded by the
National Cancer Institute and began to assemble a team of physicians, nurses, and support staff
that remains largely intact to this day. During the early 1970s, Thomas and his group developed
many of the clinical techniques that established hematopoietic cell transplantation as a lifesav-
ing treatment for large numbers of patients. For his pioneering work Thomas has received
almost every possible prize, including, of course, the 1990 Nobel Prize in Medicine, which
he shared with Dr. Joseph Murray. On receipt of every award, Thomas is quick to point out
the contributions of other scientists to the field of transplantation. He never fails to credit the
nursing and support staff workers who have been so much a part of this effort, and he always
acknowledges the patients and their families who have been partners in his work. While
hematopoietic cell transplantation might have developed as a therapeutic tool without Tho-
mas’ contribution, it would not have happened nearly as quickly or become as effective as it
is without his leadership.
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10. Thomas ED, Lochte HL, Jr., Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving
radiation and chemotherapy. N Engl J Med 1957;257:491–496.
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1958;181:1735,1736.
16. Thomas ED, Collins JA, Herman EC, Jr., Ferrebee JW. Marrow transplants in lethally irradiated dogs given
methotrexate. Blood 1962;19:217–228.
17. Epstein RB, Storb R, Ragde H, Thomas ED. Cytotoxic typing antisera for marrow grafting in littermate dogs.
Transplantation 1968;6:45–58.
18. Storb R, Epstein RB, Graham TC, Thomas ED. Methotrexate regimens for control of graft-versus-host disease
in dogs with allogeneic marrow grafts. Transplantation 1970;9:240–246.
19. Storb R, Rudolph RH, Thomas ED. Marrow grafts between canine siblings matched by serotyping and mixed
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20. Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked
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21. Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bone-marrow transplantation in a patient with the
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22. deKoning J, van Bekkum DW, Dicke KA, Dooren LJ, Radl J, van Rood JJ. Transplantation of bone-marrow
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23. Thomas ED, Buckner CD, Storb R, et al. Aplastic anaemia treated by marrow transplantation. Lancet
1972;i:284–289.
24. Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy,
total body irradiation, and allogeneic marrow transplantation. Blood 1977;49:511–533.
25. Thomas ED, Buckner CD, Clift RA, et al. Marrow transplantation for acute nonlymphoblastic leukemia in first
remission. N Engl J Med 1979;301:597–599.
26. Kurnick NB, Montano A, Gerdes JC, Feder BH. Preliminary observations on the treatment of postirradiation
hematopoietic depression in man by the infusion of stored autogenous bone marrow. Ann Intern Med
1958;49:973–986.
27. McGovern JJ, Jr., Russel PS, Atkins L, Webster EW. Treatment of terminal leukemic relapse by total-body
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Med 1959;260:675–683.
28. Appelbaum FR, Herzig GP, Ziegler JL, Graw RG, Levine AS, Deisseroth AB. Successful engraftment of
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29. Appelbaum FR, Deisseroth AB, Graw RG, et al. Prolonged complete remission following high dose chemo-
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47. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for
prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med
1986;314:729–735.
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parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet.1981;ii:327–331.
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50. Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant granulocyte-macrophage colony-stimulating
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52. Goodrich JM, Mori M, Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease
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Chapter 2 / Allogeneic BMT for AML 11
II DISEASE INDICATIONS:
ALLOGENEIC TRANSPLANTATION
12 Part II / Disease Indications: Allogeneic Transplantation
2 Allogeneic Hematopoietic Cell

Transplantation for Adult Patients
with Acute Myelogenous Leukemia
Henry C. Fung, MD and Stephen J. Forman, MD

CONTENTS
INTRODUCTION
CYTOGENETIC CHARACTERIZATION OF AML
PATIENTS WITH POOR RISK CYTOGENETICS
MYELODYSPLASTIC SYNDROMES
TRANSPLANT STRATEGY FOR ADULT PATIENTS WITH AML
WHEN TO BEGIN CONSIDERATION FOR BMT
OUTCOME AFTER BMT FOR AML
EFFECT OF CONDITIONING REGIMEN ON SURVIVAL OR RELAPSE RATE
ALLOGENEIC BMT FOR AML IN FIRST RELAPSE OR CR2
RECOMMENDATIONS FOR ALLOGENEIC BMT FOR AML
ALLOGENEIC TRANSPLANTATION FOR MDS
FACTORS INFLUENCING OUTCOME
IPSS SCORE AND RESULTS OF BMT FOR MDS
EVIDENCE FOR GVL EFFECT
NONMYELOABLATIVE ALLOGENEIC BMT (MINI-BMT)
APPROACH TO THE PATIENT WITH PRIMARY REFRACTORY AML
INNOVATIONS IN ALLOGENEIC TRANSPLANTATION FOR AML
ACKNOWLEDGMENT
REFERENCES
1. INTRODUCTION
The role of allogeneic marrow transplantation in the management of acute leukemia has
grown considerably since the initial reports many years ago describing the safe infusion of
marrow cells into humans with acute myelogenous leukemia (AML). A landmark report by
Thomas describing 100 patients with acute leukemia beyond first remission, including 54 cases
of AML treated with a total body irradiation (TBI) containing regimen and an allogeneic
transplant, showed the curative potential of the therapy (1). The use of bone marrow transplan-
tation (BMT) for AML has expanded in the past three decades and has moved from an experi-

13
mental treatment used only for patients with refractory disease to a first line of treatment for
patients with AML in their first remission, depending on biological characteristics and re-
sponse to initial therapy, as described here (2–6). This chapter summarizes the data on the
results of allogeneic transplantation for AML, interpreted within the context of the evolving
understanding of the molecular biology and cytogenetics of AML, and the implications of
these disease-related factors in the treatment and long-term survival in patients with this
disease.
Historically, the classification of treatment of AML has been based completely on morpho-
logic and clinical observations; however, the identification of the molecular events involved
in the pathogenesis of human tumors has refined their classification and understanding, includ-
ing the acute leukemias (7). In AML, a large number of leukemia-specific cytogenetic abnor-
malities have been identified, and the involved genes cloned. These studies have helped
elucidate the molecular pathways that may be involved in cellular transformation, provided
methods for monitoring of patients after chemotherapy, and helped evaluate the response to
therapy correlated with various clinical and phenotypic characteristics (8). Although the leu-
kemia cells in many patients do not have detectable structural chromosome abnormalities at
diagnosis, some may show molecular changes at diagnosis, such as involvement of the MLL
gene (9). Taken together, these observations have led to the concept that AML is a heteroge-
neous disease with its variants best defined by molecular defects and cytogenetic changes,
some of which are more common in different age groups. In previous treatment trials with
standard therapy, allogeneic and autologous transplantation, patients were often treated as a
homogeneous group. As described here, recent studies have refined the way patients are
allocated to various treatments, as well as in the analysis of the data, and provide the basis for
now making a biologically and response-based treatment decision, rather than a global one, for
patients with AML.
2. CYTOGENETIC CHARACTERIZATION OF AML

Cytogenetic risk groups form the backbone of a decision tree for postremission consolida-
tion at the present time (10–12). Other disease-related factors ,which influence the risk of
relapse after induction chemotherapy, include high leukocyte count at diagnosis or extram-
edullary disease and residual leukemia in marrow examinations 7–10 d after completion of
induction therapy. The availability of a sibling or unrelated donor also affects the risk assess-
ment for consolidation treatment. Human leukocyte antigen (HLA) typing is now part of the
National Cancer Comprehensive Network (NCCN) guideline recommendations for initial
evaluation of patients with newly diagnosed AML who do not have co-morbid medical con-
ditions, which would be a contraindication to transplantation.
Patients with acute promyelocytic leukemia (APL) enjoy an excellent disease-free survival
(DFS) (80–90%) with current conventional dose chemotherapy combined with All-
transretinoic acid (ATRA) in induction and maintenance (13,14). Remission status can be
monitored by following the level of the fusion protein promyelocytic leukemia/retinoic recep-
tor alpha (PML/RARα) produced by the t(15;17) translocation using polymerase chain reac-
tion (PCR) techniques (14). Patients who either fail to achieve molecular remission by
completion of consolidation or who show re-emergence and a rising level of the fusion protein
are likely to relapse. Transplantation, using either an allogeneic donor or a molecular negative
autologous stem cell product, is reserved for patients with APL who show evidence of relapse.
Patients with good risk cytogenetics [t(8;21), inv(16), t(16;16)] may achieve long-term
remission with multiple cycles of high dose 1-β-D-arabinofuranosylcytosine (ARA-C) in 50–
60% of patients with relapse as the major cause of treatment failure (15). Autologous transplant
following one or more dose intensive chemotherapy consolidations have shown somewhat
better DFS of 70–85% in cooperative groups and single institution studies (16). Although
molecular probes exist for these translocations, their use in monitoring minimal residual dis-
ease is not as clinically useful as the probes for chronic myeloid leukemia (CML) or APL (17,18).
Many patients with t(8;21) in clinical remission remain PCR positive for 10–20 yr without
relapse. Thus, the treatment approach for consolidation therapy of this subgroup of patients
would include either: (i) multiple cycles of high dose ARA-C (HDAC) with allogeneic transplant
reserved for treatment of relapse in patients having a sibling donor; (ii) one or two cycles of high
dose ARA-C (HDAC) followed by autologous peripheral blood stem cell transplantation
(PBSCT) in complete remission (CR); or (iii) multiple cycles of HDAC with autologous stem
cells collected in remission and reserved for salvage in patients without a sibling donor.
The majority of adults with de novo AML are in the intermediate risk group. Unfortunately,
the DFS for this group declines to 30–35% when HDAC alone is used for consolidation. In this
group of patients, both autologous and allogeneic (sibling) transplant in CR offer an improved
DFS of 50–60% (19–21). Factors that might influence the type of transplant are patient age,
tumor burden at diagnosis and infectious complications during induction. In younger patients
(≤30 yr) in whom the risk of graft-vs-host disease (GVHD) is relatively low, allogeneic trans-
plantation may be more attractive due to a low (15–20%) relapse rate. In an older patient (50–
60 yr), the higher treatment-related mortality (20–40%) and long-term morbidity associated
with allogeneic marrow transplant suggests that autologous PBSCT offers at least an equiva-
lent chance of relapse-free survival with less long-term toxicity. Recent studies using PBSCs
rather than marrow in the allogeneic setting have shown a significant decrease in the toxicity
profile of dose-intensive regimen, which may make these treatments safer in older patients but
longer follow-up is needed (22). In addition, the development of nonmyeloablative allogeneic
transplant approaches may allow for the use of allogeneic BMT in older patients with AML as
described in more detail later in this chapter.
3. PATIENTS WITH POOR RISK CYTOGENETICS

Patients with loss of chromosomes 5 or 7 or complex karyotypic abnormalities, as well as
those patients with antecedent myelodysplasia or therapy-related leukemia have a very poor
outcome when treated with conventional HDAC (10–12% 5-yr DFS). Autologous transplants
have failed to improve on these results in most series. Allogeneic transplants can cure approx
40% of patients in this group (1,23). In patients with any of these poor risk features who lack
a sibling donor, an unrelated donor search should be initiated early while the patient is still
undergoing induction.
4. MYELODYSPLASTIC SYNDROMES
The myelodysplastic syndromes (MDSs) encompass a spectrum of marrow disorders with
variable degrees of ineffective hematopoiesis and predisposition to leukemic transformation
with survival ranging from months to decades after diagnosis (24). Factors influencing the
outcome are the number of significant cytopenias, cytogenetic abnormalities, and presence of
increasing marrow blasts, which have recently been codified into a prognostic index that
reflects both the survival and leukemic transformation as described below (25). While the
majority of patients with MDS are above 60 yr of age and, therefore, above the usual age for
transplant, there are an increasing number of younger patients developing MDS as a sequelae
of chemotherapy or radiation for lymphomas, germ cell tumors, and breast cancer (26,27).
These secondary MDS patients tend to be at high risk for early transformation to AML and
often have poor risk cytogenetics.
Decisions to utilize transplantation to replace the defective stem cells are influenced by the
patient’s age, prognostic index score, and co-morbid conditions (28). Patients with low risk
disease are usually not recommended for transplant until they progress, unless they have
treatment-related MDS. For patients with intermediate risk disease allogeneic transplant from
a sibling or volunteer unrelated donor should be considered as primary therapy for patients
under 55; such procedures successfully restore normal hematopoiesis in 40–50% of patients.
For patients with high risk disease (with ≥15% blasts in the marrow) or secondary AML, there
is controversy as to whether induction chemotherapy to reduce the “leukemic” burden is
beneficial. Whereas the relapse rate is less in patients who respond to induction treatment, there
are also many who fail to respond and who become too debilitated to receive a transplant. In
patients who do not have a sibling donor, induction chemotherapy may be necessary as a
temporizing measure while a donor is sought.
As described below, there is also interest in exploring nonmyeloablative transplant for older
patients with AML and for those patients with intermediate risk MDS. While the early mor-
bidity of this approach is low, much longer follow-up will be needed to learn whether the
allogeneic graft-vs-leukemia (GVL) effect can be utilized to improve the outcome for these
patients.
5. TRANSPLANT STRATEGY FOR ADULT PATIENTS WITH AML

Anthracycline containing primary induction therapy for newly diagnosed AML will lead to
CR in 65–80% of patients treated (7). The likelihood of remaining in CR is, however, highly
dependent on prognostic factors found at the time of diagnosis, including cytogenetic analysis
as well as response to treatment. Patients who require more than one cycle of chemotherapy
to achieve remission have a poor prognosis regardless of cytogenetic subgroup (29). Subsequent
treatment options for patients who successfully enter first CR (CR1) after primary induction therapy
include: (i) repeated courses of intensive consolidation chemotherapy; (ii) autologous bone marrow
transplantation; or (iii) allogeneic bone marrow transplantation.
Currently, the decision on which of the above options to choose should take into account the
predicted benefit in terms of DFS and quality of life vs risk of morbidity and mortality. An important
component of this decision depends on identification of an available matched sibling donor. In most
series, allogeneic transplantation results in a lower rate of relapse for patients undergoing BMT for
AML in first remission (2). These results, however, do not always factor in the new information on
the biology of AML and the impact of various treatment modalities on the outcome.
Compared to autologous transplantation or consolidation chemotherapy, allogeneic BMT
carries with it a higher potential for complications, with particular difficulty arising from
regimen-related toxicity, infection, and GVHD, but offers the therapeutic potential of GVL
effect (Table 1). Decision making should also take into account the knowledge that AML
treated by allogeneic transplantation at the time of relapse is less likely to induce a lasting
remission than transplantation at the time of first remission, because the disease may become
treatment-resistant, accompanied by the development of additional somatic mutations and
drug resistance. Patients who relapse and who are then treated with chemotherapy may develop
organ dysfunction, as a result of chemotherapy or treatment for fungal or bacterial infections
and become less able to withstand subsequent chemotherapy or a BMT preparative regimen.
The decision to proceed to allogeneic transplantation thus becomes less controversial as
patients move from lesser to greater risk of relapse (and risk of death from leukemia), i.e.,
beyond CR1, and toward first relapse (R1) , second complete remission (CR2), or for primary
refractory disease. Much research has, therefore, centered on the determination of which
patients are the most likely to benefit from allogeneic BMT early on in their treatment course.
Table 1
Comparison of Allogeneic vs Autologous Stem Cell Transplant
Allogeneic Autologous
Advantages Advantages
1. No tumor contamination of graft and 1. No need to identify donor if peripheral blood and/or
no prior marrow injury from marrow uninvolved by tumor at time of collection.
chemotherapy (less risk of late MDS).
2. Graft-vs-tumor effect. 2. No immunosuppression equals less risk of infections.
3. Can be used for patients with marrow 3. No GVHD.
involvement by tumor or with bone
marrow dysfunction such as aplastic
anemia, hemoglobinopathies, or prior
pelvic radiation.
4. Dose-intensive therapy can be used for older patients
(usually up to age 70).
5. Low early treatment related mortality (2–5%).
Disadvantages Disadvantages
1. Dose-intensive regimen limited by 1. Not feasible if PBSC/marrow involved.
toxicity (usually to patients <55).
2. Time to identify donor if no sibling 2. Possible marrow injury leading to late MDS (either
donor available and/or limited from prior chemotherapy or transplant regimen).
availability of donor for some
ethnic groups.
3. Higher early treatment-related 3. No graft-vs-tumor effect.
mortality from GVHD and infectious
complications (20–40% depending
on age and donor source).
4. Not all patients can be mobilized to give adequate cell
doses for reconstitution
6. WHEN TO BEGIN CONSIDERATION FOR BMT

Because AML carries with it a high risk of relapse after achievement of remission, patients
under the age of 60 who have no obvious contraindications for allogeneic blood or BMT
(ALLOBMT) should be evaluated regarding the number, health, and availability of siblings
or other close relatives who are potential candidates for bone marrow donation. HLA typing
can be performed at any time, but should be performed early so that all treatment options can
be defined, particularly if the patient does not achieve a remission. This applies particularly
to patients with poor risk cytogenetics or other poor prognostic features who are at very high
risk for early relapse. This approach provides for minimal delay for transplantation in the
possible event of primary refractory disease, early disease relapse after primary therapy, or
persistent cytogenetic abnormalities in the marrow after CR is attained. In addition, there is
currently no evidence that consolidation therapy used before proceeding to allogeneic trans-
plant has any benefit in reducing relapse after allogeneic transplant (30). Thus, for patients
in a first morphologic and cytogenetic remission who are candidates for allogeneic BMT,
consolidation therapy is not necessary and may lead to complications that either delay or
increase the risk of transplantation.
Fig. 1. Actuarial relapse rate for patients undergoing allogeneic transplantation for AML in first remis-
sion with a regimen of fractionated TBI and VP-16. Based on pretransplant cytogenetics, those patients
with poor risk cytogenetics showed a higher rate of relapse compared to those with more favorable
cytogenetic findings.
7. OUTCOME AFTER BMT FOR AML

Studies demonstrate a 5-yr DFS of 46–62% for patients treated with allogeneic BMT in CR1
(31–35). In a representative study from City of Hope National Medical Center and Stanford
University, 61 consecutive patients with AML in CR1 under age 50 with a histocompatible
sibling donor received, an allogeneic BMT, after conditioning with fractionated TBI (1,320
cGy) and high-dose etoposide (60 mg/kg) (36). The patients with AML demonstrated a 3-yr
DFS of 61% with a relapse rate of 12%. By stepwise Cox regression analysis, significant
prognostic variables for patients with AML were the presence of acute GVHD, increasing age
and the cytogenetic risk category of the AML at the time of diagnosis (36,37). Relapse was 0%
in patients with good risk cytogenetics and approached 40% in those patients with poor risk
cytogenetics (37) (Fig. 1). Complications related to GVHD and relapse of leukemia were the
major causes of death. Additional studies from multiple institutions support a DFS ranging
from 46 to 62% after 5 yr of observation (38–43).
In order to reduce the limitations of GVHD on survival, Papadopoulos and colleagues at
Memorial Sloan-Kettering Cancer Center studied the use of T-cell-depleted allografts in 31
patients with AML in CR1 or CR2. Patients treated in CR1, attained a DFS of 77% at 56 mo,
while those treated in CR2 had a DFS of 50% at 48 mo. All patients were treated with a
conditioning regimen of TBI, thiotepa, and cytoxan. Probability of relapse in patients treated
in CR1 was 3.2%. Nonleukemic mortality in this group was 19.4%. There were no cases of
grade II–IV acute GVHD (44).
8. EFFECT OF CONDITIONING REGIMEN ON SURVIVAL OR RELAPSE RATE

Several studies have been published comparing outcome after different conditioning regi-
mens. Although the use of higher doses of TBI results in a lower rate of relapse, patients
suffered a higher incidence of GVHD and transplant-related mortality (45). Other studies have
found no significant differences between conditioning regimens using cyclophosphamide
(CY)/single-dose TBI vs CY/fractionated-dose TBI (FTBI), chemotherapy (CT)/TBI vs
melphalan/TBI (28). There are conflicting data as to whether busulfan (BU)/CY results in a
higher relapse rate than CY/TBI, but recent data suggest that optimal use of BU (intravenous
or targeted therapy) may have an impact on both toxicity and relapse (46). Recent studies
utilizing radioimmunotherapy designed to target hematopoietic tissue have shown promising
results with a low relapse rate and no increase in transplant-related toxicity (47). Presently,
there are no data to determine whether one regimen is more or less effective for each of the
cytogenetic subtypes of AML.
9. ALLOGENEIC BMT FOR AML IN FIRST RELAPSE OR CR2

For patients in relapse after failure of standard therapy for AML, allogeneic transplantation
offers the only chance for cure for those patients who have a sibling donor. For those patients
who are able to achieve a second remission, particularly after a long first remission and a lack
of a sibling donor, an autologous transplant is a potentially curative therapy (48,49). A common
dilemma is the question of whether to proceed directly to allogeneic transplantation at the time
of relapse (if a suitable donor has been identified) or whether to proceed to reinduction che-
motherapy first, in an attempt to reach a second CR (required for autologous BMT). Although
no randomized data are available, one study demonstrates statistically nonsignificant survival
rate differences of 29% in patients transplanted in untreated first relapse vs 22% in second
remission and in 10% with refractory relapse (2,50,51). Another study retrospectively evalu-
ated outcomes in patients transplanted at various stages of disease. DFS was significantly
better in patients transplanted in first remission, but no statistical difference was found between
the various groups transplanted beyond first CR. Thus, the decision concerning reinduction is
often based on the age, condition, duration of first remission, and cytogenetic category of the
patient with relapsed AML (2).
10. RECOMMENDATIONS FOR ALLOGENEIC BMT FOR AML

Information on cytogenetics at the time of diagnosis is vital to identify patients who might
have a good prognosis after standard chemotherapy, as opposed to those who should have
allogeneic transplant during first complete remission. Those who should be considered for
standard consolidation therapy or autologous transplantation include those with t(8;21) or
inv(16), in the absence of any other poor prognostic indicators for these subtypes. Other
patients should be strongly considered for allogeneic BMT during first CR.
For those patients with poor prognosis and who lack a matched family donor, alternative
donors (matched unrelated donors, cord blood transplants) should be pursued (52,53).
Figure 2 shows an approach to the timing and use of BMT based on prognostic features
found at diagnosis and response to treatment (2).
11. ALLOGENEIC TRANSPLANTATION AND MDS

Because MDS is not curable with conventional treatment, feasibility studies of allogeneic
transplantation began in the 1980s. Reports from several groups showed that the disease could
be cured by allogeneic BMT (54,55).
Fig. 2. Proposed algorithm for treatment of adults diagnosed with AML based primarily on cytogenetic
analysis of the patients’ leukemia at the time of diagnosis. CR, complete remission; PR, partial remis-
sion; IF, induction failure; ALLOBMT, allogeneic bone marrow transplantation; AUTOBMT, autolo-
gous bone marrow transplantation; MUD, matched unrelated donor.
A large retrospective survey of the European Group for Blood and Marrow Transplantation
(EBMT) Leukaemia Working Party describes 78 patients with myelodysplasia (MDS) or
secondary acute myelogenous leukemia (sAML) that received an allogeneic BMT (56). The
status of underlying disease at the time of transplantation was prognostic for the 2-yr DFS.
Thirty-four patients received intensive chemotherapy prior to the conditioning for BMT. The
2-yr DFS was 60% for the 16 patients transplanted in CR. The results were significantly less
favorable for those with more advanced disease who only partially responded prior to intensive
chemotherapy (2-yr DFS: 18%), while none of those who either relapsed or were resistant to
chemotherapy became long-term survivors after BMT. Forty-four patients had not received
any prior intensive chemotherapy. The DFS at 2 yr after BMT was 58 ± 19% when a patient
was transplanted for refractory anemia with ringed sideroblasts (RARS), 74 ± 14% for refrac-
tory anemia with excess blasts (RAEB), 50 ± 16% for RAEB in transformation (RAEB-T), and
18 ± 11% for secondary AML. Allogeneic BMT can, therefore, be considered as a potential
curative treatment for patients with MDS.
12. FACTORS INFLUENCING OUTCOME

Initial studies involving allogeneic transplant for MDS focused mainly on the feasibility of
the procedure, but lacked the statistical power to evaluate the effect of factors such as timing
of transplantation, cytogenetics, or disease status on outcome. Addressing the question of
which pretransplant factors are most predictive of favorable posttransplant outcome, the
Chronic Leukemia Working Party of the EBMT retrospectively analyzed 131 patients who
underwent BMT for MDS from HLA-identical siblings (57). No patient received prior remis-
sion induction chemotherapy. The 5-yr DFS and overall survival (OS) for the entire group of
patients was 34 and 41%, respectively. DFS and OS were dependent on pretransplant bone
marrow blast counts. Patients with RA/RARS, RAEB, RAEB-T, and sAML had a 5-yr DFS
of 52, 34, 19, and 26%, respectively, while the 5-yr OS for the respective patient groups was
57, 42, 24, and 28%, respectively. In a multivariate analysis, younger age, shorter disease
duration, and absence of excess of blasts were associated with improved outcome.
13. IPSS SCORE AND RESULTS OF BMT FOR MDS

Several classification systems have been used for evaluating prognosis in patients with
MDS, including the French–American–British (FAB) system. The International MDS Risk
Analysis Workshop performed a global analysis on clinical data from seven large previously
reported risk-based studies that had generated prognostic systems. The International Prognos-
tic Scoring System (IPSS) was developed by evaluating critical prognostic variables and, in
particular, by using a more refined bone marrow cytogenetic classification. A multivariate
analysis combined these cytogenetic subgroups with percentage of bone marrow blasts and
number of cytopenias to generate a prognostic model. Weighting these variables by their
statistical power separated patients into four distinctive subgroups of risk. Patients receive a
separate score based on percentage of marrow blasts, karyotype, and information on cytopenias.
These scores are then combined into a total score which is then used to predict progression to
AML, as well as for median survival (58).
Appelbaum et al., analyzed data for all MDS patients transplanted in Seattle from 1981 to
1996, using multivariate analysis to determine factors predictive for nonrelapse mortality,
relapse, and DFS. A total of 251 MDS patients were transplanted (59). The IPSS score corre-
lated significantly with relapse and DFS. The 5-yr DFS was 60, 36, and 28% for low- and
intermediate-1 risk, intermediate-2 risk, and high-risk patients, respectively, leading to the
conclusion that patients with intermediate-1, intermediate-2, or high-risk MDS are most likely
to benefit from early transplantation.
14. EVIDENCE FOR GVL EFFECT

It has been recognized for some that the therapeutic benefit and potential cure achieved by
allogeneic transplant is contributed by the dose-intensive regimen of either high-dose chemo-
therapy or high-dose chemotherapy and radiation combined with a graft-vs-tumor effect (60).
Over time, the potency of the graft-vs-tumor effect has been further understood and represents
a significant immune-mediated effect to prevent relapse after the high dose chemotherapy and
allogeneic stem cell transplant. Data that support the presence of GVL effect after allogeneic
transplant include:
1. Reduced risk of relapse in patients with acute and chronic GVHD.
2. Detection of minimal residual disease early after transplantation, which clears over time.
3. Increased risk of relapse after syngeneic transplant.
4. Increased risk of relapse after T-cell-depleted transplants.
5. Induction of remission by donor lymphocyte infusions in patients relapsing after BMT.
Among hematologic malignancies, there are major differences in their susceptibility to the
graft-vs-tumor effect, with CML being the most potent target; however, for patients with AML
undergoing allogeneic transplantation, compared to syngeneic transplant, the relapse rate is
lower following allogeneic transplant, suggesting that the allogeneic effect on AML is contrib-
uting to the long-term benefit (61). This observation provides the basis for the exploration of
nonmyeloablative transplants in patients with AML, particularly those older persons with
AML in whom the disease is more common, but in whom allogeneic transplantation has not
been commonly utilized.
15. NONMYELOABLATIVE ALLOGENEIC BMT (MINI-BMT)

The high-dose chemotherapy and radiation typically used in the conditioning regimens for
BMT produces considerable morbidity and mortality and limits the use of this modality to
those patients who are young and have medical conditions that would preclude its use. With
regard to AML, although allogeneic transplantation has been an effective therapy in younger
patients, it has not been utilized in older patients where the disease is not only more common,
but the biology of the disease is different. Older patients with AML often have worse cytoge-
netics and phenotypes, such as expression of multidrug resistance that correlate with a decreased
response to therapy and poor OS and DFS (62). Given the role of the GVL effect in curing some
hematologic malignancies, an alternative strategy has evolved to utilize low dose non-
myeloablative conditioning regimens designed to provide sufficient immune suppression to
achieve engraftment of an allogeneic blood cell or marrow graft, thus facilitating the develop-
ment of a graft-vs-malignancy effect. The generation of a GVL effect requires engraftment and
ultimate in vivo expansion of donor immunocompetent cells that can recognize allogeneic
target antigens including both the normal and abnormal marrow of the recipient. The overall
goal of this approach is to facilitate less intensive conditioning regimen treatment that would
be associated with decreased regimen-related toxicity and to allow a graft-vs-tumor effect (63).
This approach has been utilized by a number of investigators with varying regimens from a
pure nonmyeloablative regimen utilizing TBI and fludarabine followed by posttransplant
mycophenolate mofetil (MMF) and cyclosporin, to more intensive ones utilizing busulfan,
fludarabine, and antithymocyte globulin with encouraging results (64). A study from a consor-
tium of centers exploring a purely nonmyeloablative regimen has shown that the overall
mortality in a group of patients whose median age was 60 at d 100 was 10%, half of which is
contributed by disease progression (65). Thus, this approach is being explored for patients with
AML, particularly those who are older and have poor risk features, such as high white count,
more than two cycles of therapy to go into remission, multidrug resistance (MDR) phenotype,
or poor risk cytogenetics.
16. APPROACH TO THE PATIENT WITH PRIMARY REFRACTORY AML

The survival of patients with AML who do not achieve a remission with primary therapy is
very poor and, in general, is independent of all other cellular characteristics. The lack of
achievement of remission is the clearest demonstration of the resistance of the disease to
chemotherapy. Some studies have been performed which indicate that the use of allogeneic
transplantation in patients who have not achieved a remission may result in long-term DFS in
approx 15–30% of patients (66–68). In a recent analysis of 71 patients with primary refractory
AML who underwent an allogeneic BMT, an analysis was performed to determine whether
there are pretransplant features of this unique patient population that predict treatment outcome
(69). Although relapse and regimen-related toxicity was high in this high-risk patient popula-
tion, the probability of DFS and relapse at 3 yr was 29 and 54%, respectively. Remarkably,
unfavorable cytogenetics before stem cell transplantation was significantly associated with
decreased DFS and a TBI-based regimen appeared to convey a better outcome. The actuarial
probability of DFS and relapse at 3 yr was 44 and 38% for patients with intermediate cytoge-
netics and 18 and 68% for those patients with unfavorable cytogenetics. Figure 3 shows the
DFS for a group of patients who failed to achieve a remission and were then treated with an
allogeneic BMT.
The data suggest that allogeneic transplantation can cure some patients with primary refrac-
tory AML and that cytogenetic analysis before stem cell transplantation correlates with trans-
Fig. 3. DFS for a group of patients with AML undergoing allogeneic transplantation after having failed
to achieve a remission with either conventional dose of ARA-C or high-dose ARA-C and an
anthracycline. Patients with intermediate cytogenetics had a better DFS than those with unfavorable
cytogenetics. Overall, the actual probability of DFS at 3 yr was 44% for patients with intermediate
cytogenetics and 18% for those with unfavorable cytogenetics.
plant outcome as well as relapse. Thus, for patients who do not achieve remission with either
one or two cycles of induction therapy, particularly with a high-dose ARA-C-based regimen,
proceeding to allogeneic transplantation when a sibling donor is identified appears to be the
optimal strategy rather than utilizing repeated courses of chemotherapy, which are unlikely to
result in remission. Patients who require more than one cycle of chemotherapy to achieve a
remission should also be considered at high risk for relapse and should be considered for early
BMT (8).
17. INNOVATIONS IN ALLOGENEIC TRANSPLANTATION FOR AML

Although the most common regimens, namely, FTBI and CY, BU and CY, and FTBI and
etoposie (VP-16) have a long and stable track record, studies are being conducted to improve
both the toxicity profile and efficacy of the regimens utilized in the treatment of AML. In
general, TBI-based regimens have been more effective than non-TBI regimens, but have more
toxicity to gastrointestinal (GI) mucosa and may be more associated with increased risk of
second malignancies over time. Studies are being performed with the use of radio-
immunoconjugates utilizing anti-CD45 or anti-CD33 antibodies conjugated to a variety of
radioisotopes including iodine and yttrium. Early studies suggest the addition of radio-
immunoconjugates to a regimen of BU and CY is an effective approach without, as yet,
increasing toxicity (70). Phase II studies are ongoing in AML with this approach, but the early
data would suggest that incorporation of the radioimmunoconjugate into the preparative regi-
men is tolerable and will require further studies to determine the impact on preventing relapse
in the various subgroups of AML.
In addition, the optimal use of chemotherapy as part of the preparative regimen is receiving
increasing attention based on observations concerning the different pharmacokinetic and
pharmacogenetic disposition of these agents in individual patients undergoing transplantation.

Most recently, studies utilizing the intravenous form of BU have shown a better toxicity profile
and less individual variation in the area under the plasma concentration vs time curve (AUC)
achieved by the drugs (71). Studies performed in CML and myelodysplasia suggest that tar-
geting the dose of BU, either orally or intravenous, not only improves the toxicity profile and
facilitates the use of these regimens in patients with myelodysplasia who are older, but has an
impact on the risk of relapse (72).
Nonmyeloablative transplantation, as noted above, which utilizes the immunotherapeutic
effect of allogeneic T-cells, is being explored in older patients with AML and, depending upon
the results, could be applied in younger patients with AML, particularly those for whom
retaining fertility is an important consideration. In addition, the use of a nonmyeloablative
approach may be utilized as immunotherapy following an autologous transplant for AML to
help combine the benefits of the high-dose regimen utilized with autologous transplantation
with the immunotherapeutic contribution of the allograft.
The stem cell source also may contribute to the overall benefit of allogeneic transplantation.
Studies have been performed, comparing peripheral blood to marrow, that demonstrate the
improved hematopoietic recovery and decreased toxicity without an obvious increase in
acute or chronic graft-vs-host reaction (22). Further studies are being performed to deter-
mine the incidence and extent of chronic GVHD in patients receiving PBSCT and the use of
this cellular product is now being explored in patients with AML undergoing transplant in first
remission.
ACKNOWLEDGMENT
This work was supported in part by United States Public Service Grants NCI PPG CA 30206
and NCI CA 33572.
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Chapter 3 / Stem Cell Transplantation for ALL 29
3 Allogeneic Stem Cell Transplantation

for Adult Acute Lymphoblastic Leukemia
Partow Kebriaei, MD and Wendy Stock, MD

CONTENTS
INTRODUCTION
PROGNOSTIC FACTORS IN ADULT ALL
ALLOGENEIC TRANSPLANTATION FOR HIGH-RISK ALL DURING FIRST CR
ALLOGENEIC TRANPLANTATION BEYOND CR1 USING HLA-IDENTIFIED
SIBLING DONORS
PRIMARY REFRACTORY ALL
PHILADELPHIA CHROMOSOME-POSITIVE ALL
FACTORS INFLUENCING TRANSPLANT OUTCOME
LONG-TERM COMPLICATIONS OF ALLOGENEIC TRANSPLANTATION
NOVEL TRANSPLANT APPROACHES
REFERENCES
1. INTRODUCTION
Current treatment strategies for adult acute lymphoblastic leukemia (ALL) have resulted in
the achievement of complete remission (CR) rates of 70–95%. Approximately 25–50% of
these patients may enjoy long-term disease-free survival (DFS), and current research efforts
are focused on innovative postremission strategies with the goal of improving the overall
survival for adults with ALL. The identification of different prognostic groups based on the
biology of the malignant clone and clinical patterns of disease presentation has begun to alter
our therapeutic approach to this biologically heterogeneous disease. Treatment strategies tai-
lored to specific prognostic groups have already resulted in dramatic improvements in the
outcome for children with ALL (1), and similar risk-adapted strategies based on the biologic
heterogeneity of the disease are now being applied to adults with ALL to improve survival.
Allogeneic stem cell transplantation (SCT) is one strategy that has been demonstrated to
improve the outcome of high-risk adults with ALL. In this chapter, we will define this high-
risk group, discuss indications for transplantation based on biologic risk group, and review
current strategies and clinical outcome for allogeneic SCT in adults with ALL.
2. PROGNOSTIC FACTORS IN ADULT ALL

Several biologic features and specific clinical characteristics have been consistently noted
to influence the outcome of adult ALL and impact on risk stratification (Fig. 1). Age greater

29
Fig. 1. Adverse prognostic features in adult ALL.
than 60 yr, a high white blood cell count (WBC) at presentation, and failure to achieve a clinical
remission within the first 4 wk of treatment are all considered adverse clinical features. The
detection of specific recurring cytogenetic abnormalities has emerged as the most important
prognostic factor for risk stratification of adults with ALL. Clonal chromosomal aberrations
can be detected in cells from 62 to 85% of adult ALL patients, and several studies have shown
their significance as predictors of outcome (2,3). In a multivariate analysis of risk factors in
adult ALL, karyotype was identified as the most important factor for DFS (4). In general,
patients with a normal karyotype have improved survival compared with those harboring a
cytogenetic abnormality. In a recent review of this literature, six abnormalities were noted to
result in unfavorable outcome, defined as having a 0.25 or less probability of continuous CR
at 5 yr. These include in decreasing frequency, patients with t(9;22) (q34;q11), trisomy 8,
t(4;11) (q21;q23), monosomy 7, a hypodiploid karyotype, and t(1;19) (5,6).
The most common and clinically relevant cytogenetic abnormalities in adults with ALL
include the t(9;22) (q34;q11) resulting in the BCR/ABL fusion gene that is present in as many
as 30% of adult ALL patients, the t(4;11) (q21;q23) involving the MLL gene on chromosome
11q23 that results in the MLL/AF4 fusion gene, and the t(8;14) (q24;q32) chromosomal trans-
location seen in mature B lineage ALL (Burkitt’s type) that results in overexpression of the c-
MYC proto-oncogene. With each of these abnormalities, patients have improved outcome if
they are treated with an approach other than standard induction, consolidation, and mainte-
nance regimens. For example, treatment insights from the pediatric groups have resulted in the
successful implementation of fractionated high doses of alkylating agents in combination with
high dose methotrexate and intensive central nervous system prophylaxis to improve signifi-
cantly the outcome for adults with mature B-CR to use B-cell ALL (7–10). Using this intensive
but short-duration chemotherapeutic approach, these high-risk patients now achieve CR in 70–
80% of cases and have DFS approaching 50%. As described above, and discussed in detail
below, ALL patients with a t(9;22) (q34;q11) have fared very poorly with standard ALL
chemotherapy, but can achieve prolonged DFS when allogeneic SCT approaches are used.
A number of investigators have combined these prognostic factors to predict the efficacy of
the planned chemotherapy and to assess the potential use of allogeneic transplantation for
patients with ALL. Hoelzer et al. initially proposed a risk classification of adult ALL focusing
on age, WBC count, immunophenotype, and time to achievement of CR (4). This classification
scheme identified patients who had either good long-term DFS or poor outcome with a high
risk of relapse. Similarly, Table 1 shows the impact of four adverse features and the outcome
of treatment of ALL in two studies of intensive combination chemotherapy from the Cancer
and Leukemia Group B (CALGB studies 8811 and 9111) (10,11). This analysis demonstrates
that a large number of adults with ALL have disease features at diagnosis that put them into
a high-risk group with a DFS of less than 30%. These types of analyses, combined with
advances in cytogenetic and molecular monitoring techniques to detect minimal residual dis-
ease (MRD) (discussed below), are useful for the identification of patients who might benefit
from early hematopoietic SCT while in first remission.
Table 1
Impact of Adverse Features on the Outcome of Treatment
No. of adverse No. of Age WBC No medstinal Laboratory Estimated
a
features patients <60 yr <30,000/µL mass features survival at 3 yr
0 22 0 0 0 0 91% (66–98%)
1 83 1 16 63 3 64% (51–75%)
2 146 12 25 145 110 49% (36–61%)
3 89 25 68 89 85 21% (12–35%)
4 13 13 13 13 13 0
a
Adverse laboratory features include the presence of the Ph or BCR/ABL+ PCR analysis, L3 morphology, or
precursor B lineage disease.
2.1. Prognostic Role of MRD Monitoring

In addition to the adverse prognostic factors listed in Table 1, the detection of MRD using
qualitative or semiquantitative polymerase chain reaction (PCR) or flow cytometric tech-
niques is also beginning to provide important prognostic information. A number of large
prospective studies in pediatric ALL have demonstrated the independent prognostic signifi-
cance of MRD detection. Using semiquantitative PCR for the detection of the leukemia “clone-
specific” immunoglobulin heavy chain or T cell receptor gene rearrangement, these studies
have shown that persistent MRD detection at various time points following achievement of
morphologic and cytogenetic remission is a highly significant and independent prognosticator
of relapse (12,13). Less is known about the significance of MRD detection in adult ALL. Brisco
et al. studied 27 adults with B lineage ALL for MRD in CR1. Eight of nine patients with higher
levels of disease (levels >10–3) detected using semiquantitative PCR relapsed, compared to 6
of 13 patients with lower MRD levels (levels <10–3) (14). Larger, prospective studies are
currently underway using more precise quantitative PCR (real time PCR) to determine the
significance of MRD detection in predicting relapse in adult ALL (15). These data may provide
critical new prognostic information about “low risk” patients in CR1 who are actually at high
risk for relapse and identify a new group of patients who might benefit from allogeneic SCT
while still in first remission.
3. ALLOGENEIC TRANSPLANTATION FOR HIGH RISK ALL

DURING FIRST CR
Several studies have investigated allogeneic SCT approaches in high-risk ALL patients
following achievement of first CR (Table 2). These studies are difficult to compare directly
with results of trials utilizing postremission chemotherapy, since the transplant series are
usually small phase II studies that tend to include only healthy, younger patients who are
already in remission. Nevertheless, a number of these trials provide some interesting insights
into the potential efficacy of allogeneic SCT in CR1. To better clarify the relative roles of
chemotherapy and SCT in adults with high-risk ALL, Horowitz et al. analyzed International
Bone Marrow Transplant Registry (IBMTR) data for 484 patients who had received intensive
postremission chemotherapy, and 251 recipients of HLA-identical allogeneic SCT for ALL in
CR1. Patients ranged from 15 to 45 yr of age and were treated between 1980 and 1987. Similar
prognostic factors, including non-T lineage phenotype, high leukocyte count at presentation,
and greater than 8 wk to achieve CR, predicted treatment failure in both treatment groups. After
statistical adjustments were made for differences in disease characteristics, 5-yr leukemia-free
survival (LFS) was similar in the chemotherapy (38%) and allogeneic SCT (44%) cohorts;
Table 1
Comparative Trials of Transplantation vs Chemotherapy for ALL in CR1
No. of Median GVHD 5-yr
Study patients age (yr) Prep. regimen proph. II–IV GVHD DFS (%)
Horowitz, 1991 (16)
ASCT 234 15–45 CY/TBI MR NR 44
Chemotherapy 484 15–45 MR 38
Rowe, 1999 (17)
ASCT 173 14–60 VP-16/TBI NR NR 58 (3 yr)
Chemotherapy/ 426 14–60 39 (3 yr)
aSCT
Sebban, 1994 (LALA 87) (17)
ASCT 116 26 CY/TBI CSA/MTX NR 45
Chemotherapy/ 141 24 CY/TBI for SCT 31
aSCT L10 regimen
Thiebaut, 2000 (LALA 87 f/u) (18)
ASCT 116 15–40 CY/TBI CSA/MTX NR 46
High risk 41 44
Standard risk 75 49
Chemotherapy 141 ≤50 L10 regimen 31
High risk 55 11
Standard risk 86 43
Oh, 1998 (19)
ASCT 87 >30 CY ± Ara-C/TBI CSA/MTX NR 30
Chemotherapy 38 >30 MR 26
ASCT 127 <30 CY ± Ara-C/TBI CSA/MTX NR 53
Chemotherapy 38 <30 MR 30
ASCT, allogeneic SCT; aSCT, autologous SCT; CY, cytoxan; TBI, total body irradiation; MR, multiple
regimens; NR, not reported; VP-16, etoposide; CSA, cyclosporine; MTX, methotrexate.
however, causes of treatment failure differed between the two groups. In the chemotherapy
group, 96% of failures were due to relapse and 4% were treatment-related, while in the SCT
group, 32% were due to relapse and 68% were treatment-related (16). Thus, while there was
no difference in overall survival, this retrospective analysis suggests a decreased risk of relapse
for high-risk patients treated with allogeneic SCT in CR1.
The MRC UKALL XII/ECOG E2993 is an international effort to prospectively define the
role of allogeneic SCT, autologous SCT, and chemotherapy in adult patients with ALL in CR1.
Initiated in 1993, over 1100 patients have been enrolled to date (HM Lazarus, personal com-
munication, May 2001). All patients received two phases of induction therapy, and continued
to allogeneic SCT if they achieved CR and had a histocompatible donor. The remaining
patients were randomized to standard consolidation/maintenance therapy for 2.5 yr vs a single
autologous SCT. The conditioning regimen for both allogeneic and autologous transplants was
fractionated TBI (1320 cGy) and VP-16 (60 mg/kg). Available date on the first 800 patients
revealed a CR rate of 91% for Philadelphia (Ph) patients and 83% for Ph+ patients; these results
are corroborated by earlier, smaller trials. Details regarding the reponse of Ph+ patients to
standard therapy vs allogeneic SCT will be discussed in the section on Ph+ patients. Based on
the data presented in an abstract published in 1999 (17), 173 patients received an allogeneic
SCT and 426 patients received chemotherapy or autologous SCT. The overall event free
survival (EFS) for the allogeneic SCT group was 58 vs 39% for the chemotherapy or autolo-
gous BMT group. When patients (excluding Ph+ patients) were stratified into high or standard
risk, the difference in EFS becomes more dramatic in the high risk subset (allogeneic BMT
57% vs chemotherapy/autologous BMT 32%), illustrating the advantage of allogeneic BMT
in high risk patients. Standard risk was defined as Ph__, age <35, time to CR <4 wk, and WBC
count <30,000/µL for B lineage and <50,000/µL for T lineage leukemia.
The French (Leucemie Aigue Lymphoblastique de l’Adulte [LALA]) group is another
cooperative study which defined the role of chemotherapy and SCT for adult ALL patients.
This was a prospective randomized study, initiated in November 1986 and completed in
July 1991, which enrolled 634 patients in the LALA 87 protocol to assess the role of
allogeneic SCT and autologous SCT in adult ALL. After exclusions, 572 patients were
analyzed, and 10-yr follow-up results have recently been published. The median age of
patients entered onto this trial was 33 yr. Patients received induction chemotherapy with
cyclophosphamide, vincristine, prednisone, and one of two anthracyclines. Central ner-
vous system (CNS) prophylaxis was administered. Four hundred and thirty-six patients
(76%) achieved CR. After CR was achieved, patients older than 50 yr received
postremission chemotherapy. Patients between 15 and 40 yr of age were assigned to the
allogeneic SCT trial if they had an HLA-matched sibling donor. Patients between ages 40
and 50, and those under the age of 40 without a matched sibling donor, were further
randomized to consolidation chemotherapy or autologous SCT using bone marrow purged
with antibodies or mafosfamide. Consolidation chemotherapy consisted of three monthly
courses of daunorubicin or zorubicin, Ara-C, and asparaginase followed by long-term
maintenance therapy. The transplant preparative regimen consisted of total body irradia-
tion (TBI) and cyclophosphamide. The 10-yr overall survival rate of patients greater than
50 yr treated with chemotherapy only was 27%. There was no statistically significant
difference in outcome between patients who received autologous SCT vs consolidation
chemotherapy (34% SCT, 29% chemotherapy, p = 0.6). After stratification into high and
standard risk, there was still no statistical difference between these two groups. High risk
was defined as having one or more of the following factors: presence of the Ph chromo-
some, null ALL, age > 35 yr, WBC count > 30 × 109/L, time to CR >4 wk. Importantly,
this study showed that survival at 10 yr was significantly greater for the allogeneic SCT
group compared to consolidation chemotherapy (46% SCT, 31% chemotherapy, p = 0.04).
Furthermore, when these groups were stratified into high and standard risk, there was a
highly significant benefit for allogeneic SCT in the high-risk subset, but no statistically
significant benefit seen for the standard-risk subset (high risk: 44% SCT, 11% chemo-
therapy, p = 0.009; standard risk: 49% SCT, 43% chemotherapy, p = 0.6) (18,19). Thus,
both the large IBMTR retrospective review and the LALA study suggest a clear role for
allogeneic SCT over consolidation chemotherapy in younger adults with high-risk fea-
tures in CR1. Another study by Oh et al. reinforces the observation that a significant
survival advantage is gained in high-risk younger patients undergoing allogeneic SCT
(20). Presumably, the lower mortality and morbidity sustained by younger patients under-
going SCT highlights the advantage of this method over chemotherapy.
In addition, review of a number of smaller phase II trials in high-risk adult ALL who have
undergone ASCT in CR1 suggest a higher DFS when compared with conventional chemo-
therapy (21–27). High risk in these studies was defined as patients having at least one or more
of the following: age greater than 30 yr, WBC greater than 30 × 109/L at presentation,
extramedullary disease, unfavorable cytogenetic abnormalities, and requiring more than 4 wk
to achieve a CR. As shown in Table 3, these phase II trials demonstrate a DFS ranging broadly
from 21–71% during a 3- to 8-yr follow-up. The DFS for patients treated with conventional
chemotherapy ranges from 30 to 40%. The large difference in outcome of patients entered onto
these small phase II studies is influenced by multiple variables, including differences in patient
Table 3
Allogeneic Transplantation for ALL in CR1
No. of Median GVHD 3-yr
Study patients age (yr) Prep. regimen proph. II–IV GVHD DFS (%)
Wingard, 1990 (20) 18 24 (5–36) CY/TBI CSA ± MP 8 42
Blaise, 1990 (21) 25 22 (4–36) CY/fTBI, ML/fTBI MR 7 71
CY/ML/fTBI
Chao, 1991 (22) 53 28 (1–45) Ara-C/CY/TBI CSA ± MP 6 61
CY/TBI MTX ± MP
Doney, 1991 (23) 41 22 (18–50) Cy/fTBI or MR 7 21 (5 yr)
single dose
Sutton, 1993 (24) 184 25 (15–44) CY/TBI MR 15 deaths 49.5 (6 yr)
(retrospective review) (majority)
Vey, 1994 (25) 29 24 (16–41) CY/TBI CSA/MTX 7 62 (8 yr)
DeWitte, 1994 (26) 22 15–51 CY/TBI CSA NR 58
CY, cytoxan; fTBI, fractionated total body irradiation; MR, multiple regimens; NR, not reported; CSA,
cyclosporine; MTX, methotrexate; MP, methylprednisolone.
selection, choice of preparative regimen, type of graft-vs-host disease (GVHD) prophylaxis,

and different supportive care regimens.
4. ALLOGENEIC TRANSPLANTATION BEYOND CR1 USING HLA-IDENTICAL

SIBLING DONORS
There are no data suggesting that durable remissions can be achieved with standard chemo-
therapy for adults with ALL in/or beyond CR2. Similar to the transplant literature in pediatric
ALL beyond first remission, it appears that allogeneic SCT for adults in/beyond CR2 is supe-
rior to chemotherapy in achieving LFS. Adult ALL patients who undergo an allogeneic SCT
in CR2 achieve long-term LFS rates of 14–43%, as illustrated in Table 4. The primary cause
of failure is relapse (>50%).
5. PRIMARY REFRACTORY ALL

With current induction regimens, only 5–10% of adults with newly diagnosed ALL fail to
achieve remission with initial induction chemotherapy. These patients often have one or more
poor prognostic factors at presentation, and additional attempts at induction chemotherapy
may be unsuccessful. Several studies suggest that patients with an HLA-identical sibling can
benefit if they proceed directly to allogeneic transplantation without undergoing a second
attempt at induction therapy (32–34). In the largest of these studies, 38 patients with ALL,
failing to achieve remission, received HLA-identical sibling transplants. Approximately 35%
of these patients with refractory disease had long-term DFS. A second study with 22 patients
(five patients with ALL) with refractory disease had a similar survival of 38% following HLA-
matched sibling transplants. Other studies suggest lower survival rates of 20% or less for these
refractory patients (32,34); nevertheless, allogeneic transplant should be considered for these
patients with an otherwise dismal chance of long-term survival.
6. PHILADELPHIA CHROMOSOME-POSITIVE ALL

The presence of the Philadelphia chromosome (Ph) represents an independent adverse risk
factor, and carries an exceptionally poor prognosis. Although many patients can achieve a CR,
Exploring the Variety of Random
Documents with Different Content
Courtesy Universal Pictures Corporation.
Staging a Movie Prize-Fight.
Notice how each actor in the foreground has to play his part, no matter how
unimportant. To make the scene realistic, each “extra” must appear as
interested as any spectator at a real prize-fight.
But let us pass on beyond the outer offices, and see where the girl
with the collie went.
Through a hallway we come suddenly into a vast, dark, cavernous
interior, high and wide and shadowy. From somewhere off at our left
comes a sound of hammering, where a new “set” is being erected.
Off at the right is more hammering and pounding with the squeaking
of nails being drawn as another set, in which the “shooting” has been
finished, is being “struck,” or taken down. From a far corner of the
great cavern there is a radiance of bluish-green light, where one of
the companies is “working.”
Curiously enough, this huge dark place is called the “light” stage. It
gets its name from the fact that scenes can be photographed on it
only with artificial light.
All about is a labyrinth of still standing sets—here a corner of a
business office, and just beyond the interior of a drawing room in a
rich home, with a beautiful curved stairway mounting ten feet or so
into nothing at the right. Next comes the corner of a large restaurant.
Under the guidance of an assistant director, in the glare of a single
bluish-green Cooper-Hewitt “bank” turned on as a work light,
property men are “dressing” it. They are putting yellow table-cloths
on the tables (in the finished picture they will look white; in reality
they are yellow instead of white in order not to be too glaring, before
the picture can be exposed long enough to bring out the contours
and details that are more important in the darker places); and
hanging a row of horse-race pictures along the wall.
This is a big studio, supposed to be making a dozen or more
pictures at once. We are surprised that on this whole great dark
“light” stage only one company is working; we learn that two others
are “shooting” elsewhere on the lot; one in back of the carpenter
shop, where a clever director has found an ideal “location” for his
purpose right under his nose, and another on one of the big
“daylight” stages that we shall see presently. Several other
companies are out on location miles from the studio—one perhaps in
another State on a trip that will last a couple of weeks. Still others
are not at the “shooting” stage of their picture at all; one or two are
still “casting,” one that follows the methods used by Griffith is “in
rehearsal,” and still others are merely waiting while scenario writer
and director work out the final details of the scenario or “continuity,”
or while the director “sits in” with the cutter or “screen editor” and title
writer to put the finishing touches on the completed product.
We go over to the corner where the one company on the big stage
is “shooting.” A dozen people are sitting around on chairs or stools,
just outside the lights. About in the middle of them, with a whole
phalanx of lights at right and left, two cameras are set up. Beside
them, in a comfortable folding camp-chair with a back rest, sits the
director. He is wearing what a humorous writer has called the
“director’s national costume” of soft shirt, knickerbockers, and
puttees. On the floor beside his chair is a megaphone.
If you hold your hands together with the palms flat, making a
narrow angle about a third of a right angle, you can get an idea of
what a camera “sees.” This angle is called the “camera angle.” Only
what happens within that narrow angle will be recorded on the film.
Sometimes white chalk-lines are drawn on the floor to mark the
camera angle; what is within the lines will be photographed, while
what is outside will not show.
Along the sides of this open space that the camera will photograph
are ranged the bright white carbon lights and the bluish-green
vacuum lights that illumine the scene. Overhead, suspended by
heavy chains from tracks that traverse the ceiling of the great stage,
are more lights; white carbon “dome” lights, and additional bluish-
green Cooper-Hewitt “overhead banks.”
Courtesy Brown Bros.
How a Motion Picture Interior is Made.
A mass of complicated paraphernalia is necessary to light and equip a
motion-picture stage. The tall lights with the lines across them are the
“Cooper-Hewitts,” or vacuum lights, called “banks.” The smaller square
lights are the white arc-lights or “Kliegs.” The snake-like cables on the floor
carry the electricity.
Courtesy W. W. Hodkinson Corporation.
Engine Trouble on a Dakota Prairie.
To get the scenes shown in this story of a transcontinental tour the motion-
picture company travelled almost across the continent.
Courtesy Goldwyn Pictures Corporation.
When the Hero is the Captain of a Steam Shovel.
Note how the reflectors, seen at the bottom of the picture, are tilted down to
throw the light up into the face of the engineer, while the camera is raised to
the right place on a platform.
Thin bluish smoke, like vapor, curls outward and upward from
most of the white carbon lights. They give off a good deal of heat. A
couple of spot-lights like those used in theaters are situated on
scaffolding higher than a man’s head, behind the cameras to left and
to right, with an attendant in charge of each.
In the bright glare the faces of all who are not “made up” with
grease paint and powder look greenish yellow. All color values are
distorted. Tan-colored shoes look green.
A scene has just been taken. The assistant director turns to an
electrician. “Kill ’em!” he says. The electrician goes to the different
lights, pulling switches to “cut ’em off.” In a moment only one of the
bluish-green “double banks” is left to serve as a working light. This is
to save electricity, of which the array of lights takes an enormous
amount.
The scene that has been taken is, we will say, of an old-fashioned
New England sitting room. In the center is a marble-topped table. In
a far corner is a “what-not,” with marble shelves. There is a
bookcase against one of the walls, and old prints and lithographs are
hung here and there. In one place is a needlework “sampler,” with a
design and motto.
The director is talking with the two actresses who were in the
scene. They are in costumes of the Civil War period, with flounces
and hoopskirts. They are supposed to be sisters.
Suddenly the director decides to take the scene over again. He
has thought of a bit of more effective action that will get the point he
is trying to make in the story over more effectively. “We’ll shoot it
again,” he says. “Let’s run through it once more first.”
The two actresses, already thoroughly familiar with the scene,
rehearse it again, adding the new bit of detail as the director instructs
them. He is not quite satisfied, and takes one of the parts himself,
showing the actress how he wants her to put her hand up to her
face. Finally she does it to suit him, and he is satisfied. “All right,” he
says, “we’ll shoot it.—Lights!”
The lights are switched on once more, and in the bright, sputtering
glare the sisters walk into the scene. Just before they cross the line
into the camera angle both camera men start grinding.
After about fifteen seconds of action the director nods, well
pleased. “Cut!” he says shortly, and both camera men stop.
Half an hour’s preparation and rehearsal for fifteen seconds of
action!
Again the lights are switched off. The man in charge of the script,
sitting on a stool with a sheet of paper snapped on a board on his
lap, puts down the number of the scene and adds details of costume
—what each sister is wearing, the flowers that one is carrying in her
hand, and so on—to have a complete record in case of “retake,” or
other scenes that match with this before or after.
“Now we’ll move up on ’em,” says the director. The cameras are
moved closer, and the action of the preceding scenes is repeated.
This time the cameras are so close that the faces of the actresses
will appear large on the screen, with every detail of expression
showing. Before the close-ups are begun, the lights are moved up,
too, and one of the spot lights switched around more to one side to
give an attractive “back lighting” effect on the hair of the sisters, that
appears almost like a halo, later, when it is seen on the screen.
Before each scene is taken an assistant holds a slate with the
director’s name, the head camera man’s name, and the number of
the scene, written on it, in front of the cameras, and the camera men
grind a few turns. In this way, the “take” is made.
When the different “takes” are finally matched together in the
finished picture these numbers will be cut off, but they are necessary
to facilitate the work of identifying the hundreds or even thousands of
different shots of which the final picture is composed.
Leaving the great dark “light stage” we pass on into the lot beyond.
In front of us is another great stage, but this time open to the sky.
Instead of artificial lights, there are great white cloth “reflectors,” to
deflect the sunlight on to the scene and intensify the light where
under the sun’s direct rays alone there would be shadows.
Sets, actors, camera men and action are all as they were on the
other stage, except that instead of a profusion of sets we find here
only one or two, as not nearly so many scenes are taken here as on
the other stage.
Formerly nearly all scenes were taken in sunlight, and studios
were built that had no provision for lighting except the sun. But while
the film industry was still in its infancy the development of artificial
lighting made possible results that could not be secured with sunlight
alone, and since that time artificial lighting is used on most motion-
picture scenes that represent “interiors.”
About us on the “lot” are other stages, covered with glass, that lets
in the sunlight but keeps out the rain, so that work may go on
uninterruptedly. On most of these a combination of natural and
artificial light is used—electric lights as in the “light stage,”
supplemented by daylight.
We pass on to the property houses—great buildings like
warehouses ranged one behind the other. In one place we find a
room where modeling is going on; skilled artists are making statues
that will be used in a picture depicting the life of a sculptor. In
another place special furniture is being made. One great warehouse-
like building is devoted to “flats” and “drops,” of which the differing
sets can in part, at least, be built. Then there are the costume rooms,
and the “junk” rooms, with knick-knacks of all descriptions.
You’d be amazed to know how many properties are needed in the
making of even the simplest motion pictures. Take, for instance, the
set that we have already described—an old New England sitting-
room. The furniture, the marble-topped table and the what-not with
its marble shelves and the chairs and possibly a hair-cloth sofa, were
of course obvious. The old prints and lithographs and even the
sampler, hardly less so; but in addition to these, think of the
ornaments that would have to appear on the what-not shelves and
the kind of lamp that would be on the table and what books there
would have to be in the bookcase. Without these details, the room
would not look natural.
Take a look around the room where you are reading this page.
Notice how many little things there are that you would never think of
arranging, if you were to have carpenters and property men
reconstruct it for you as a set for a picture. Newspapers—all the
hundred and one little things, left here and there, that go to make a
home what it is—even to the scratches on the walls, or the corner
knocked off one arm of a chair.
Courtesy United Artists Corporation.
Douglas Fairbanks as D’Artagnan in “The Three Musketeers.”
Here are presented all three basic characteristics of a good story—
fascinating characters engaged in stirring action, at an interesting time and
place. Note the careful details of costuming, and decorations of the old
furniture.
Courtesy United Artists Corporation.
Another Scene from “The Three Musketeers.”
See how even the flagstones of this narrow alley of
Old France have been reproduced with faithful care.
The property man of a famous director once told me: “I’ve got the
greatest collection of junk in the whole business. Just odds and
ends. No one thing in the whole outfit worth anything in itself, but the
King (he was referring to the director) would be crazy if he sold it for
ten thousand dollars—yes, or twenty-five thousand, either. I tell you,
sometimes junk is the most important thing in a picture.”
After a set has been built, it is usually “dressed” by hiring first the
furniture from one of the concerns that have grown up for just this
purpose—renting furniture, old or new, to motion-picture companies
that want to use it for a few weeks. If, in addition to what has been
rented, the producing company is able to supply bits of “junk” from its
own property room and make the set look more natural, so much the
better.
The story is told of one enterprising concern in Los Angeles that
started in collecting beer-bottles just after prohibition went into effect.
Since the bottles were no longer returnable, they were able to buy
them here and there for almost nothing, until they had on hand a
tremendous supply. The word went around that such and such a
concern was in the market for bottles, and every boy in Los Angeles
gathered up what he could find and took them around while the
market was still good. People thought they were crazy, and had a
good laugh at the movie industry that didn’t know any more than to
buy up hundreds and hundreds of old beer-bottles that nobody would
ever be able to use again.
Then one of the producing companies wanted a batch of bottles
for some bar-room scene and found that they didn’t happen to have
any on the lot. They went to the big property concern that they
usually traded with, only to find that they, too, didn’t happen to have
any beer-bottles. So they went to the concern that had been buying
them all up at junk prices.
Certainly they could have some bottles—all they wanted! They
would be thirty cents a week each, and a dollar apiece for any that
were broken or not returned. Take it or leave it!
The corner on old beer-bottles had suddenly become profitable.
The producing company tried to get bottles elsewhere and beat the
monopoly—but time was pressing. When the overhead of a single
company is running at hundreds of dollars a day, a property man will
not be forgiven if he holds up the whole production while he scours
the city to save money on beer-bottles. The price was paid.
But let us get on with our tour of the studio. We have not yet come
to one of the most important places of all—the laboratory where the
film is developed.
The laboratory work of many producing companies is not done on
the lot at all, but is sent away to one of the big commercial
laboratories that does work for many different companies. But
several of the larger producers have their own laboratory plants.
In the laboratory we visit first the developing-room, feeling our way
cautiously into the dark around many corners that cut off every
possible ray of light from outside. Walking on wet slats we reach at
last the chamber in the middle of what seems to be an almost
impenetrable labyrinth, and in the dim red light can barely make out
the vats where the strips of celluloid, wound back and forth on
wooden hand-racks, are being dipped into the developer.
Nowadays many of the laboratories are equipped with complicated
developing machines, that combine all the processes of developing,
washing, “fixing,” and drying in one. Where prints, made from the
original negative, are being developed, tinting is added. The
undeveloped film, tightly wound in small rolls, is threaded through
one end of the developing machine in the dark-room; it travels over
little cog-wheels that mesh into the holes at the edges of the film,
and goes down into a long upright tube filled with developer. Coming
back out of this, still on the cogs, it travels next down into a tube of
clear water for washing. Then down into another tube containing
“hypo,” and up again for another tube and second washing. Then,
still winding along on the little cogs it travels through a partition and
out into a light room, where it passes through an airshaft for drying,
across an open space for inspection, and is finally wound into as
tight a roll as it started from in its undeveloped state.
In the printing-room, still in the dim red light, we see half a dozen
printing-machines at work, with raw film and negative feeding
together past the aperture where the single flash of white light makes
the exposure that leaves the negative image upon the print.
Next, in daylight once more, we see the great revolving racks of
the drying-room used for film developed by the hand process—with
hundreds of feet of the celluloid ribbon wrapped around and around
great wooden drums.
In the assembling-room we find girls at work winding up strips of
film and cementing or patching the ends of the film together to make
a continuous reel.
Another room is more interesting still. This room is dark once
more, with a row of high-speed projection machines along one side
and a blank wall on the other. Here the finished film, colored and
patched, receives its final inspection. Against the white wall four or
five pictures are flickering simultaneously. Since the projection
machines are only a few feet away from the white surface that acts
as a screen, each picture measures only two or three feet long and
two-thirds as much in height. In one picture we may see a jungle
scene; alongside it a reel of titles is being flashed through, one after
another; next to this again is the “rush stuff” for a news reel with the
president shaking hands so fast it looks as if he had St. Vitus dance;
next comes a beautifully colored scenic, and at the end of the row
the dramatic climax of a “society film,” rushing along at nearly double
its normal theater speed.
Leaving the laboratory, we pass down a street, bordered on one
side by a row of little boxlike offices that are used by the directors of
the different companies; opposite, in a similar row of offices, the
scenario writers are housed. The end of the street brings us back
once more to the building that houses the administrative offices
through which we came when we entered.
If we had time we could visit the menagerie that lies at the rear of
the studio proper, and that makes even the line-up of a circus tent
look tame. Or, we could spend a day watching the company shooting
the storm scene at the back edge of the lot, where the customary old
airplane propeller has been mounted on a solid block with a motor
attached and backed up alongside the scenes to furnish a gale of
wind.
But we have already seen enough for an introduction.
To make a six-reel picture takes from three or four weeks to twice
as many months and costs all the way from ten or fifteen thousand
dollars to half a million, and sometimes even a million. You can
imagine the investment required where a producing organization is
running ten or a dozen companies at once, each turning out pictures
at top speed.
Only the other day one of the Hollywood studios changed hands at
the sale price of three-quarters of a million dollars. Some are worth
twice that amount.
But it is not the size of the investment that counts. It is the quality
of the finished product. That is the thing we want to look farther into.

Filming an Old Engineer on a Fast-Moving Locomotive.
Notice how close director and assistant director are to the line of the
“camera angle.” The director using a small megaphone to overcome the
noise of the train and the rushing air.
Another Railroad Scene.
The umbrella put up to shade the company gives an idea of the length of
time often necessary to take even the simplest scenes. Hours, possibly, were
spent at this one spot.
CHAPTER V
MAKING A MOTION PICTURE
Once I was turned loose in New York City with thirty-odd thousand
dollars and a novel by a popular author, and told to make a movie
out of them.
Suppose that should happen to you. How would you begin?
Of course you would want to make a better picture than so many
of these other fellows seem able to turn out. But how would you
start? Just by hiring some actors and a camera man and telling them
to get busy?
It is not so easy as that.
The first thing for me, to be sure, was getting together the men
who would help make the photoplay. Re-writing the story into a
scene-by-scene continuity, hiring a studio and attending to all the
business details, selecting a cast, picking out the “locations” for
scenes, designing the “sets” and supervising the construction of
them, and “directing” the scenes, is more than any one person can
do. The Swiss Family Robinson itself couldn’t do it alone.
So I selected and hired a director, and a camera man, and a
continuity writer, and an art director to design the sets. That took
quite a while.
Then the trouble began.
The director decided he wanted an assistant director; the camera
man decided he wanted an assistant camera man; the art director
decided that I didn’t know what I was doing, and the “owners”
decided that everything done so far was all wrong.
That brought out two very interesting things about motion pictures
that apply to lots of other businesses as well. And sports, too, if you
like, and almost everything else.
The first is the matter of coöperation.
When the rowers in a boat pull only when they feel like it, the boat
goes wabbling all over the place, instead of straight ahead, and
everybody gets his knuckles barked. Everybody has to pull together.
Imagine a football team without any teamwork!
Movies are so complicated, in the making, that dozens of people,
hundreds often, have to pull together when they are being made.
That very thing is one of the big reasons why moving pictures to-
day aren’t any better than they are. Mostly movie people haven’t yet
learned to pull well together, or how exceedingly important it is in the
making of pictures.
If you can’t work with other fellows without bucking and kicking,—
don’t ever try motion-picture work.
The other trouble was with the owners. There were too many
bosses on the job, which always makes a mess.
That quaint, humorous philosopher, “Josh Billings,” once said, “It
ain’t ignorance that makes so much trouble; it’s so many people
knowing too many things that ain’t so.”
With movies, that’s an ever-present danger.
Mostly, we’re all of us so sure of things, that we saw or heard or
thought or remember, that we just know we’re right, about this or
that, and can’t be wrong. If we know a little bit about surveying, we
feel we can tell surveyors how to survey, and so on. And the less we
know about a thing (as long as we do know something about it) and
the more indefinite that thing and the knowledge about it are, the
more we think we know about it.
Take stories: when you read one, you know whether you like it or
not; but could you tell how it would be apt to strike other people? It’s
easy to think you can do that—and most motion-picture producers
and financiers are sure they can. But as a matter of fact, an editor,
trained for years in the selection of stories, could probably do a lot
better.
In motion pictures, the man who puts up the money for a
production has to be pretty wise to realize how much less he
probably knows about motion pictures than the men he hires to
make the pictures for him.
As yet, few owners or producers of motion pictures know enough
to keep their hands off all the things that they ought to leave to their
employees.
Well, to get back to this particular movie.
We got another director, and then decided to give him an assistant
after all. And we got another camera man—and then gave him an
assistant. We got a cast, and started off to the city where most of the
work was to be done.
I say “we.” That is correct. The owners insisted on “sitting in” on
everything, so that each decision was a compromise, instead of
being the best judgment of the one they had hired to make that
picture for them.
When we came to taking the first scenes we made a discovery.
Our hero was a sissy.
He looked like a regular fellow—we had every reason to suppose
he was at least as much of a regular fellow as most actors can be.
But he threw a baseball the way a girl does.
He couldn’t even throw a custard pie. Luckily we didn’t want him
to. But we did want him to look and act like a man’s man, and mostly
it was mighty hard for him.
He had fifteen or twenty different suits, but no sign of a tennis-
racket, or baseball glove, or golf-stick.
He couldn’t drive an automobile. But he was supposed to be a
wonderful actor—just the man to play a hero!
Then, along came the property man.
You will remember that a chain is no stronger than its weakest link.
A motion picture, that is made by the combined efforts of a whole
group of people, all pulling together, is much the same way. If any
one of the group, on whom some particular duty depends, is
ignorant, or inexperienced, or lazy, or pig-headed, the defects of his
work will mar the finished film.
If the actors can’t act well, the picture will be laughed at; if the
camera man is poor, the photography will be poor, and so on.
The property man is the one who has to see that the details of a
picture are correct; that if the hero has a handkerchief showing in his
pocket when he walks out of one scene, he has it when he walks into
the next, and so on.
When you realize that a picture is usually taken location by
location and set by set, instead of in the natural order of the scenes,
you can realize how important it is to have some one check up on all
the details.

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ALLOGENEIC STEM CELL TRANSPLANTATION

CURRENT CLINICAL ONCOLOGY

Treatment of Acute Leukemias: New Directions for Clinical Research, edited by

© 2003 Humana Press Inc.

Production Editor: Tracy Catanese

This publication is printed on acid-free paper. ∞

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Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data

15 Immune Recovery Following Allogeneic Blood Transplantation:

GINNA G. LAPORT, Division of Bone Marrow Transplantation, Stanford University Medical

1 Hematopoietic Stem Cell Transplantation

2. EARLY STUDIES LEADING TO THE FIRST HUMAN TRIALS

From: Current Clinical Oncology: Allogeneic Stem Cell Transplantation

3. INITIAL TRIALS IN HUMANS

4. LABORATORY STUDIES LEADING TO THE FIRST SUCCESSES IN PATIENTS

to be generally involved in histocompatibility. The ability to select HLA-compatible siblings

5. INITIAL SUCCESSES IN HUMAN MARROW TRANSPLANTATION

6. SUBSEQUENT ADVANCES IN THE APPLICATION

6.1. Source of Stem Cells

6.2. Preparative Regimens

6.3. Graft-vs-Host Disease

6.4. Supportive Care Techniques

7. A TRIBUTE TO E. DONNALL THOMAS

2 Allogeneic Hematopoietic Cell

Henry C. Fung, MD and Stephen J. Forman, MD

From: Current Clinical Oncology: Allogeneic Stem Cell Transplantation

2. CYTOGENETIC CHARACTERIZATION OF AML

3. PATIENTS WITH POOR RISK CYTOGENETICS

5. TRANSPLANT STRATEGY FOR ADULT PATIENTS WITH AML

6. WHEN TO BEGIN CONSIDERATION FOR BMT

7. OUTCOME AFTER BMT FOR AML

8. EFFECT OF CONDITIONING REGIMEN ON SURVIVAL OR RELAPSE RATE

9. ALLOGENEIC BMT FOR AML IN FIRST RELAPSE OR CR2

10. RECOMMENDATIONS FOR ALLOGENEIC BMT FOR AML

11. ALLOGENEIC TRANSPLANTATION AND MDS

12. FACTORS INFLUENCING OUTCOME

13. IPSS SCORE AND RESULTS OF BMT FOR MDS

14. EVIDENCE FOR GVL EFFECT

15. NONMYELOABLATIVE ALLOGENEIC BMT (MINI-BMT)

16. APPROACH TO THE PATIENT WITH PRIMARY REFRACTORY AML

17. INNOVATIONS IN ALLOGENEIC TRANSPLANTATION FOR AML

pharmacogenetic disposition of these agents in individual patients undergoing transplantation.

3 Allogeneic Stem Cell Transplantation

Partow Kebriaei, MD and Wendy Stock, MD

2. PROGNOSTIC FACTORS IN ADULT ALL

From: Current Clinical Oncology: Allogeneic Stem Cell Transplantation

Fig. 1. Adverse prognostic features in adult ALL.

2.1. Prognostic Role of MRD Monitoring