Table Of ContentLANDES
B I O S C I E N C E V
m
Richard K. Burt
Scott T. Lothian
a d e m e c u
V
LANDES
B I O S C I E N C E
a d e m e c u m
Table of contents
1. General Information
2. Transplantation
Procedures
3. Transfusion Medicine
in Marrow and Blood Cell
Transplantation
4. Cytoreduction
5. MHC and Bone Marrow
Transplantation
6. Diseases
7. Engraftment
8. General Medical Care
This is one of a new series of medical handbooks.
It includes subjects generally not covered in other handbook series, especially
many technology-driven topics that reflect the increasing influence of technology
in clinical medicine.
The name chosen for this comprehensive medical handbook series is Vademecum,
a Latin word that roughly means “to carry along”. In the Middle Ages, traveling
clerics carried pocket-sized books, excerpts of the carefully transcribed canons,
known as Vademecum. In the 19th century a medical publisher in Germany, Samuel
Karger, called a series of portable medical books Vademecum.
The Vademecum books are intended to be used both in the training of physicians
and the care of patients, by medical students, medical house staff and practicing
physicians. We hope you will find them a valuable resource.
Bone Marrow
Transplantation
9. Growth Factors
10. Infections
11. Graft-Versus-Host Disease
12. Graft-Versus-Leukemia
Effect of Allogeneic BMT
13. Toxicity
14. Outpatient Management
of Marrow and Blood Stem
Cell Transplant Patients
15. Gene Therapy
16. Medications
Appendices
All titles available at
www.landesbioscience.com
H. Joachim Deeg
George W. Santos
I SBN 1- 57059- 560- 7
9 7 8 1 5 7 0 5 9 5 6 0 8
Richard K. Burt, M.D.
Northwestern University
Chicago, Illinois, U.S.A.
H. Joachim Deeg, M.D.
Fred Hutchinson Cancer Center
Seattle, Washington, U.S.A.
Scott Thomas Lothian, R.Ph.
Northwestern Memorial Hospital
Chicago, Illinois, U.S.A.
George W. Santos, M.D.
Johns Hopkins University
Baltimore, Maryland, U.S.A.
Bone Marrow
Transplantation
iv
Bone Marrow Transplantation
Landes Bioscience
Georgetown
U.S. and Canada Copyright © 1998 Landes Bioscience
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopy, recording, or any
information storage and retrieval system, without permission in writing from
the publisher.
Printed in the U.S.A.
Please address all inquiries to the Publishers:
Landes Bioscience, 810 S. Church, Georgetown, Texas, U.S.A. 78626
Phone: 512/ 863 7762; FAX: 512/ 863 0081
Library of Congress Cataloging-in-Publication Data
Bone marrow transplantation /
[edited by] Richard K. Burt, H. Joachim Deeg, George W. Santos
p. cm.
"A vademecum series book."
Includes bibliographical references and index.
ISBN 1-57059-560-7 (alk. paper)
1. Bone marrow—Transplantation. 2. Bone marrow—Transplanta-
tion—Patients—Care. I. Burt, Richard K., 1954-
II. Deeg, Hans Joachim, 1945-. III. Santos, George W.
[DNLM: 1. Bone MarrowTransplantation. WH 300 B712 1998]
RD123.5.B6484 1993
617.4'4—dc21
DNLM/DC
98-49747
for Library of Congress
CIP
While the authors, editors, sponsor and publisher believe that drug selection and
dosage and the specifications and usage of equipment and devices, as set forth in
this book, are in accord with current recommendations and practice at the time of
publication, they make no warranty, expressed or implied, with respect to mate-
rial described in this book. In view of the ongoing research, equipment develop-
ment, changes in governmental regulations and the rapid accumulation of
information relating to the biomedical sciences, the reader is urged to carefully
review and evaluate the information provided herein.
U.S. and Canada ISBN: 1-57059-560-7
xxv
PREFACE
This book is a therapeutic manual designed as a quick prac-
tical guide and reference for houseofficers, fellows, pharma-
cists and nurses on the bone marrow transplant unit. Indica-
tions, complications, drug doses and approaches to clinical
management problems are emphasized. Requirements for a bone
marrow transplant unit are outlined. Chapters with procedures
on patient evaluation, unrelated donors, marrow processing, en-
graftment/relapse and general patient care (including outpatient)
are included along with many other pertinent concerns. Prob-
lems, such as GVHD, infection and toxicity are also discussed.
Diseases requiring bone marrow transplants, such as multiple
myeloma, lymphomas, pediatric malignancies and adult solid
tumors have chapters devoted to them.
ACKNOWLEDGMENT
To those physicians who helped guide me by their example,
thank you. To list a few: William Burns, M.D. (Medical College
of Wisconsin); Shalina Gupta-Burt, M.D. (Rush); Martin Lidsky,
M.D. (Baylor); Charles Link, M.D. (Human Gene Therapy Re-
search Institute); Edward C. Lynch, M.D. (Baylor); Henry
McFarland, M.D. (NIH); Arthur Nienhuis, M.D. (Saint Jude);
Steven Rosen, M.D. (Northwestern); George Santos, M.D. (Johns
Hopkins); H. I. Schweppe, M.D. (Baylor); and Ann Traynor,
M.D. (Northwestern). Finally, thank you to Connie and Charles
Liedske for their courage and determination.
3
History of Bone Marrow
Transplantation
George W. Santos
I) INTRODUCTION
Although there were early sporadic attempts to use bone marrow for its thera-
peutic effect in anemia and leukemia by oral, intramuscular or even intravenous
routes, the first detonation of a nuclear device on July 16, 1945 provided the major
stimulus for research in bone marrow transplantation. This research was initially
heavily supported by various government agencies that had an interest in under-
standing the pathophysiology of ionizing radiation injury in man.
II) EARLY HISTORY
Protection from the toxicity of total body irradiation (TBI) by shielding hemato-
poietic tissues in animals was initially observed by the Danish investigator Fabricious-
Moeller in 1922 and later confirmed with more extensive investigation by Jacobsen
in 1949. This provided the rationale for further experiments of Jacobsen and col-
leagues in 1951 and Lorenz and colleagues in the same year, that showed that the
systemic injection of spleen cells or marrow cells would provide the same protec-
tion from radiation lethality afforded by the shielding of hematopoietic tissue.
III) ACUTE GRAFT-VERSUS-HOST DISEASE (aGVHD)
In 1955 English workers reported that mice given syngeneic hematopoietic cells
following otherwise lethal TBI were afforded long lasting protection but that mice
given allogeneic cells engrafted, but died with a characteristic illness before 100
days. Initially this was called secondary disease. These observations were confirmed
and extended by a number of workers and by the late 1950s and early 1960s the
typical involvement of the skin, gut and liver was characterized as acute GVHD.
The small lymphocyte later identified as a T lymphocyte was eventually implicated
as the initiator of this iatrogenic disease.
It was recognized early that blood product transfusion could, because of its allo-
geneic T lymphocyte content, cause clinical and fatal aGVHD in individuals who
were at risk by virtue of their stage of development (i.e., fetus), disease (i.e., se-
vere combined immunodeficiency) or treatment (i.e., in some cases immunosup-
pressed because of chemotherapy of a malignancy). The simple measure of ex-
posing the blood products to sufficient x-irradiation was able to prevent this
problem.
Early workers noted that following marrow transplantation a marked immuno-
deficiency occurred but that a redevelopment of the immune system by donor cell
precursors proceeded in a pattern similar to a recapitulation of ontogeny. This
was quite clear in syngeneic transplants but the immunologic recovery was se-
verely impaired in allogeneic animal transplants. A more complete understanding
of this state of immunodeficiency came later in clinical studies.
Investigations in the late 1950s and early 1960s in mice and extending to the
early 1970s in canines indicated that methotrexate (MTX) administered following
transplantation could markedly decrease severe aGVHD. For many years it was
standard practice to use MTX following transplantation to decrease the severity of
GVHD. Subsequently prophylaxis for acute GVHD has been replaced with the use
1.1
Bone Marrow Transplantation, edited by Richard K. Burt, H. Joachim Deeg,
Scott Thomas Lothian, George W. Santos. © 1998 Landes Bioscience.
4
Bone Marrow Transplantation
of cyclosporine alone or with MTX or by various forms of T cell depletion of the
infused marrow.
IV) TOLERANCE
In early studies it became evident that a number of animals would eventually
recover from aGVHD. Further investigations indicated that donor lymphoid tis-
sues were specifically tolerant to host tissues. Strong evidence was presented in
experimental models that this donor to host tolerance was mediated by specific
T�lymphocyte suppressor cells of donor origin.
V) CHRONIC GVHD (cGVHD)
In the mid 1970s, the first cases of human cGVHD were reported in recipients of
HLA-identical sibling marrow allografts. Clinical manifestations were systemic in-
volving dermal, oral, ocular, hepatic, gut and pulmonary tissues. Many patients
presented with severe skin and subcutaneous fibrosis with contractures, severe
wasting and frequent infections. The disease has been associated with a number
of autoimmune phenomena. The incidence of this disease has been reported to
be between 25-50%. Initially, without treatment only about 20% of patients with
extensive cGVHD became long term survivors with a reasonable quality of life.
Earlier diagnoses and advances in treatment have markedly decreased the mor-
bidity and mortality of this complication.
VI) TRANSPLANT PREPARATIVE REGIMENS
Before the early 1970s, TBI alone was employed prior to marrow transplantation
in end stage leukemia. The Johns Hopkins group developed the rationale for the
use of high dose cyclophosphamide (CY) as a preparative regimen. Because of the
high relapse rate with both regimens they were abandoned for patients with ma-
lignancies. The CY regimen with slight modification was adopted for transplanta-
tion in severe aplastic anemia and has remained the most frequently used regimen
for marrow transplantation in that disease. In 1976 the Seattle group reported the
use of CY (60 mg/kg) given on 2 successive days followed by 1000 cGy of TBI on
the third day. Subsequently the TBI was modified as fractionated single daily doses.
With minor modifications this has been the most widely used regimen. A few other
groups, however, have further modified this regimen by the use of chemothera-
peutic agents other than CY preceding the fractionated TBI or by employing
hyperfractionated TBI.
A few transplant regimens have been employed involving only chemotherapeu-
tic agents. The most widely employed has been a combination of busulfan and CY.
In randomized studies this regimen has been shown to be as effective as the com-
bination of CY and TBI in chronic myelogenous leukemia and in acute myelog-
enous leukemia. The regimen has also been adopted in the treatment of certain
genetic diseases including thalassemia and sickle cell disease.
VII) DONORS
Initially the majority of marrow donors were genotypical HLA-identical siblings.
This provided compatible donors to only about a quarter of patients. When
phenotypic matched or one HLA antigen mismatched family members were em-
ployed as donors 30-35% of the patients were able to have a donor. Although
there is some increase in the incidence or severity of aGVHD with these donors,
the event-free survivals in the hematopoietic malignancies are the same. With
greater HLA disparity, however, the results are significantly worse. In children,
closely matched but unrelated donors (primarily phenotypically identical) have
given reasonable results (Fig. 1.1.1).
1.1
5
Although syngeneic donors are uncommon, a number of series have reported
acceptable results in the hematopoietic neoplasms and in severe aplastic anemia.
Encouraged by these results, the use of autologous bone marrow transplantation
has been pursued with renewed and increasing vigor, at first in the lymphomas,
later with the acute leukemias and more recently with various solid tumors. Au-
tologous bone marrow transplantation in carcinoma of the breast is currently the
most prevalent type of transplant for solid tumors (Fig. 1.1.2).
Although the antitumor effect demonstrated in allogeneic transplants for hema-
tologic diseases is absent with syngeneic and autologous transplants, the hazards
of morbidity and mortality associated with acute and chronic GVHD and the at-
tempts in prevention and treatment are absent. At present the increase in relapse
rate seen with autologous or syngeneic transplants is balanced against the decrease
History of Bone Marrow Transplantation
Fig. 1.1.1. Donor type for allotransplants. Reprinted with permission from IBMTR/
ABMTR 1995; 2:4.
1.1
Fig. 1.1.2. Indications for blood and marrow transplants in North America, 1994.
Reprinted with permission from IBMTR/ABMTR 1995; 2:3.
% OF ALLOTRANSPLANTS
NUMBER OF TRANSPLANTS
CML
AML
ALL
NON-
HODGKIN
LYMPHOMA
HODGKIN
DISEASE
B R E A S T
CANCER
OTHER
MALIG-
NANCY
NON-
MALIGNANT
DISEASE
Allogeneic (Total N = 4,000)
Autologous (Total N = 8,000)
6
Bone Marrow Transplantation
in toxicity associated with allogeneic transplants. In general, the overall survival
for autologous and allogeneic transplants in lymphoma and acute myelogenous
leukemia are the same.
Peripheral blood hematopoietic stem cells have more recently been shown to
be a satisfactory means of reconstituting the hematopoietic system after marrow
ablative therapy (Fig. 1.1.3). This approach offers at least two potential advan-
tages: 1) it can be collected in patients where marrow cannot be harvested be-
cause of prior damage from radiotherapy or infiltration by malignant disease and
2) it appears to produce a faster marrow reconstitution than marrow. This results
in a shorter period of neutropenia and thrombocytopenia.
VIII) CLINICAL STUDIES
Despite a few promising results, the 10 years of the late 1950s to the late 1960s
were a period of frustration and disappointment for marrow transplantation. Most
transplants were performed in terminally ill patients who died too soon for evalu-
ation of engraftment. Many of these patients were transplanted with marrow from
individuals who were not tissue typed or who were tissue typed with unreliable
methods. In cases where engraftment was successful it was followed by lethal acute
GVHD and fatal viral and fungal infections.
A dramatic improvement in the therapeutic results of allogeneic transplantation
began in the early 1970s when the definition of the HLA antigen system and more
reliable methods of tissue typing were beginning to be established. In addition,
patients with acute leukemia were being transplanted while in a complete remis-
sion rather than in florid relapse or in an infected state.
Therapeutic outcomes continued to improve during the 1970s and 80s as expe-
rience with the clinical management of transplants was acquired and advances in
supportive care, including the use of newer antibacterial, antifungal and antiviral
antibiotics, employment of hematopoietic growth factors and methods to control
serious acute and chronic GVHD were developed. Currently one might expect
cure rates of 50-90% for patients with severe aplastic anemia and various genetic
diseases, 20-70% for patients with acute leukemia, 20-80% for patients with chronic
1.1
Fig. 1.1.3. Stem cell source for autotransplants. Reprinted with permission from
IBMTR/ABMTR 1995; 2:4.
% OF AUTOTRANSPLANTS
7
History of Bone Marrow Transplantation
myelogenous leukemia or lymphoma depending on the age, clinical status of the
patient at the time of transplantation and the type and degree of tissue matching
of the donor.
IX) CONCLUSION
In the relatively short time of 3.5 decades, bone marrow transplantation has
evolved from a highly experimental laboratory activity to a well established and
curative therapeutic modality for the treatment of malignancy, diseases of marrow
failure and selected genetic diseases.
SUGGESTED READING
1. Santos GW. History of Bone Marrow Transplantation. Clin Haem 1983; 12:611-39.
2. Santos GW. Historical background. In: Atkinson K, ed. Clinical Bone Marrow Transplantation: A
Reference Textbook. Cambridge University Press, 1994; 1-9.
1.1
8
Bone Marrow Transplantation
Bone Marrow
Transplantation Unit
Philip L. McCarthy Jr., Lori A. Williams
I) REQUIREMENTS
Although autologous peripheral blood stem cell transplants may be safely per-
formed on a general hematology/oncology unit, even more recently entirely on an
outpatient basis, allogeneic bone marrow transplantation (BMT) currently remains
an investigational therapy with high mortality and should not be performed on a
regular medical or oncology floor. A BMT unit is a specialized area of the hospital
specifically designed to prevent infectious complications and provide care by a
group of nurses and physicians specifically trained in complications of intensive
chemoradiotherapy, fever, neutropenia and graft-versus-host disease. The unit may
be designed and staffed so that critically ill patients, who may require invasive
hemodynamic monitoring, mechanical ventilation and renal dialysis, can be cared
for. A BMT transplant unit is designed primarily for allogeneic patients but can be
used for autologous transplants. The use of peripheral blood as a source of he-
matopoietic stem cells has changed the character of autologous and allogeneic
transplantation. The term BMT unit will be used interchangeably for all types of
stem cell transplants. Criteria for the establishment of a transplant unit are listed
in Table 1.2.1. In the future, BMT units may require certification to assure mini-
mum standards of care. Later in this chapter, we will describe recent advances that
have allowed for the outpatient treatment of autologous patients.
A) NURSING STAFF
The first requirement for a BMT unit is a dedicated nursing staff who are
trained in the management of pancytopenic patients and are able to recognize
the complications of transplantation. The nurse to patient ratio will vary from
as low as 1:1 for a patient with multiple problems to as high as 1:3 to 1:4 for
patients who are relatively uncomplicated. Nurses must be familiar with the
administration and complications of intensive dose chemotherapy and radia-
tion therapy. Complications include veno-occlusive disease, renal failure, in-
terstitial pneumonitis, cardiac arrhythmias, hemorrhage, congestive heart fail-
ure, severe stomatitis and dermatitis as well as bacterial, fungal and viral
infections. Allogeneic transplantation also includes complications related to
immunosuppression and graft-versus-host disease, in particular organ dam-
age to skin, liver and gastrointestinal tract. Experienced nursing staff is critical
to the consistent management of BMT patients. This is especially true in units
where houseofficers and hematology/oncology fellows rotate for short peri-
ods of time. Standard orders for the management of routine problems such as
fever, administration of blood products, chemotherapy and intravenous hy-
dration facilitate the care of these complex patients and help to eliminate dis-
orientation for rotating physicians. The lack of consistent application of proto-
cols and implementation of procedures leads to unnecessary confusion and is
demoralizing for staff and others who participate in the transplant patient care.
1.2
Bone Marrow Transplantation, edited by Richard K. Burt, H. Joachim Deeg,
Scott Thomas Lothian, George W. Santos. © 1998 Landes Bioscience.
