Hematopoietic Cell Transplantation for Malignant Conditions

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vi LIST OF CONTRIBUTORS

Raynier Devillier, RD, MP, PhD Ali Haider, MD

Transplantation and Cellular Immunotherapy Unit Assistant Professor
Department of Hematology Palliative, Rehabilitation, and Integrative Medicine
Institut Paoli Calmettes, Marseille, France Houston, TX, United States
Centre de Recherche en Cancérologie de Marseille
(CRCM) Inserm UMR1068 Parameswaran Hari, MD, MS
CNRS UMR7258 Director
(3) Aix Marseille Université U105 Adult Blood and Marrow Transplant Program
Marseille, France Division of Hematology Oncology
Medical College of Wisconsin
Hematology Department
Milwaukee, WI, United States
Institut Paoli Calmettes
Marseille, France Professor
Hematology Oncology
Rebecca Devlin, PhD Milwaukee, WI, United States
Scientific Associate
Department of Medical Oncology and Hematology Chitra Hosing, MD
Princess Margaret Cancer Centre Professor
Toronto, ON, Canada Stem Cell Transplantation and Cellular Therapy
MD Anderson Cancer Center
Fiona L. Dignan, MBChB, FRCP, FRCPath, MD Houston, TX, United States
Doctor
Clinical Haematology Mohammed Junaid Hussain, MD
Manchester University Foundation Trust Plasma Cell Disorders Section
Manchester, United Kingdom Department of Hematologic Oncology & Blood
Disorders
Sabine Furst, SF, MD Levine Cancer Institute/Carolinas Healthcare System
Transplantation and Cellular Immunotherapy Unit Charlotte, NC, United States
Department of Hematology
Institut Paoli Calmettes Racquel Innis-Shelton, MD
Marseille, France Assistant Professor of Medicine
Division of Hematology and Oncology
Ragisha Gopalakrishnan, MD Department of Medicine
Hematology Oncology Fellow University of Alabama at Birmingham
Vanderbilt Ingram Cancer Center (Hematology Birmingham, AL, United States
Oncology)
Vanderbilt University Medical Center Madan Jagasia, MBBS
Nashville, TN, United States Professor of Medicine
Medicine/Division of Hematology Oncology
Alison Gulbis, PharmD, BCOP Vanderbilt University Medical Center
Manager, Clinical Pharmacy Services Nashville, TN, United States
Division of Pharmacy
MD Anderson Cancer Center Abraham S. Kanate, MD
Houston, TX, United States Assistant Professor
Osborn Hematological Malignancy and
Vikas Gupta, MD, FRCP, FRCPath Transplantation Program
Associate Professor Dept of Internal Medicine
Department of Medicine West Virginia University
University of Toronto Morgantown, WV, United States
Toronto, ON, Canada
 LIST OF CONTRIBUTORS vii

Partow Kebriaei, MD Muhammad Ayaz Mir, MBBS, FACP

Professor Chief
Stem Cell Transplant and Cellular Therapy Hematology & Oncology
MDACC Shifa International Hospital
Houston, TX, United States Islamabad, Pakistan

Maliha Khan, MD Ravi Kishore Narra, MD

Leukemia Department Assistant Professor
University of Texas Medicine, Division of Hematology/Oncology
MD Anderson Cancer Center Medical College of Wisconsin
Houston, TX, United States Brookfield, WI, United States

Shakila P. Khan, MD Nhu-Nhu Nguyen, MD

Associate Professor Physician
Pediatrics Palliative, Rehabilitation and Integrative Medicine
Mayo Clinic MD Anderson Cancer Center
Rochester, MN, United States Houston, TX, United States

Mohamed A. Kharfan-Dabaja, MD, MBA Yago Nieto, MD, PhD

Professor of Medicine Professor of Medicine
Division of Hematology-Oncology Stem Cell Transplantation and Cellular Therapy
Blood and Marrow Transplantation Program The University of Texas
Mayo Clinic MD Anderson Cancer Center
Jacksonville, FL, United States Houston, TX, United States

Sola Kim, MD Liana Nikolaenko, MD

Department of Palliative, Rehabilitation, and Assistant Clinical Professor
Integrative Medicine Hematology/Bone Marrow Transplant
University of Texas City of Hope
MD Anderson Cancer Center Duarte, CA, United States
Houston, TX, United States
Amanda Olson, MD
Mira A. Kohorst, MD Assistant Professor
Assistant Professor of Pediatrics Stem Cell Transplantation and Cellular Therapy
College of Medicine MD Anderson Cancer Center
Division of Pediatric Hematology-Oncology Houston, TX, United States
Department of Pediatric and Adolescent Medicine
Mayo Clinic Kelly E. Pillinger, PharmD
Rochester, MN, United States University of Rochester Medical Center
Strong Memorial Hospital
Amrita Krishnan, MD Rochester, NY, United States
The Judy and Bernard Briskin for Multiple Myeloma
Research Chelsea C. Pinnix, MD, PhD
City of Hope Medical Center Assistant Professor
Duarte, CA, United States Radiation Oncology
University of Texas
Rohtesh S. Mehta, MD, MPH, MS MD Anderson Cancer Center
Assistant Professor Houston, TX, United States
Stem Cell Transplantation and Cellular Therapies
The University of Texas L.M. Poon
MD Anderson Cancer Center Senior Consultant
Houston, TX, United States Hematology Oncology
National University Cancer Institute, Singapore
Singapore, Singapore
viii LIST OF CONTRIBUTORS

Kelly G. Ross, MD Benjamin Tomlinson, MD

Assistant Professor of Medicine Assistant Professor
Hematology/Oncology Internal Medicine, Division of Hematology and
West Virginia University Oncology
Morgantown, WV, United States University Hospitals Seidman Cancer Center
Cleveland, OH, United States
Muhammad A. Saif, MBBS, MRCP, FRCPath, MD
Consultant Haematologist Saad Zafar Usmani, MD, FACP
Clinical Haematology Chief
Central Manchester University Hospital Plasma Cell Disorders Section
Manchester, United Kingdom Hematologic Oncology & Blood Disorders
Levine Cancer Institute/Carolinas Healthcare System
Nirav N. Shah, MD, MS Charlotte, NC, United States
Assistant Professor of Medicine
Internal Medicine Lauren Veltri, MD
Medical College of Wisconsin Assistant Professor
Milwuakee, WI, United States Hematology/Oncology
West Virginia University School of Medicine
Zainab Shahid, MD, FACP Morgantown, WV, United States
Medical Direction Bone Marrow Transplant Infectious
Diseases Daniel Weisdorf, MD
Levine Cancer Institute Professor
Carolians Healthcare System Medicine
Charlotte, NC, United States University of Minnesota
Minneapolis, MN, United States
Bronwen E. Shaw, MBChB, PhD
Professor of Medicine Ibrahim Yakoub-Agha, MD, PhD
Hem-Onc Professor
Medical College of Wisconsin/CIBMTR Hematology
Milwaukee, WI, United States University Hospital CHRU
Lille, France
Elizabeth J. Shpall, MD
Stem Cell Transplantation and Cellular Therapy Lily Yan, PharmD, BCOP
The University of Texas MD Anderson Cancer Center Pharmacy Clinical Specialist
Houston, TX, United States Stem Cell Transplant
University of Texas
Rabbia Siddiqi, MBBS MD Anderson Cancer Center
Department of Internal Medicine Houston, TX, United States
Dow University of Health Sciences
Karachi, Pakistan

Roni Tamari, MD
Assistant Attending
Bone Marrow Transplant, Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY, United States
 SECTION I HISTORY AND BASIC SCIENCE OF
HEMATOPOIETIC CELL TRANSPLANTATION

CHAPTER 1

History and Current Status of

Hematopoietic Cell Transplantation
ROHTESH S. MEHTA, MD, MPH, MS • DANIEL WEISDORF, MD

INTRODUCTION In 1957 E.D. Thomas reported 6 attempted cases

of allogeneic BMT in patients with refractory chronic
In an atomic age, with reactor accidents, not to mention
myelogenous leukemia (CML), multiple myeloma,
stupidities with bombs, somebody is going to get more
radiation than is good for him. If infusion of marrow can
chronic lymphocytic leukemia, metastatic tumor of
induce recovery in a mouse or monkey after lethal radiation, unknown primary, metastatic ovarian tumor, and a
one had best be prepared with this form of treatment in man.1 comatose patient with massive cerebral haemorrhage.1
E. DONNALL THOMAS. Patients received conditioning with TBI, nitrogen mus-
tard, or triethylene melamine, followed by infusion of
Research in the field of bone marrow transplantation BM from either fetal or adult cadavers. Engraftment
(BMT) accelerated with the disaster caused by atomic was assessed based on the appearance of donor-type
bombs which ended World War II in August 1945. red blood cells (RBCs) in the recipient’s circulation.
Within a few months, the US government, in coordi- Although none of the patients had sustained engraft-
nation with Japanese scientists, formed a joint com- ment and only 2 patients had even temporary engraft-
mission to investigate biological effects of the bomb, ment, several noteworthy findings emerged from this
especially bone marrow (BM) failure. Comprehensive series which laid the foundation of modern hemato-
epidemiological, clinical, and genetic studies were poietic cell transplantation (HCT). First, these cases
started under the auspices of the Atomic Bomb Casu- demonstrated safety of intravenous infusion of BM
alty Commission that was formed in 1947.2,3 without concerns of pulmonary emboli. Then it was
hypothesized that prolonged engraftment could occur
BMT Developments in 1950s to Early 1960s if the dose of TBI was increased to a degree sufficient to
In 1950, Jacobson noticed “ectopic blood formation” cause marrow aplasia. It was also realized that engraft-
and rapid recovery of hematopoietic tissues in rabbits ment of allogeneic BM would fail in an individual with
treated with total body irradiation (TBI) if their spleens an intact immune system necessitating immune abla-
were shielded with lead.4 In subsequent experiments, tion before HCT as well. Finally, the remarkable finding
they witnessed increased survival of lethally irradiated was that BM could be collected and stored safely for
mice that were infused intraperitoneally with freshly future infusions.
removed allogeneic spleens as compared to mice who Two years later, E.D. Thomas reported the first cases
did not receive splenic implants.5 It was proposed that of syngeneic BMT in two children with refractory acute
if the mechanism of this enhanced hematopoietic leukemia from their twins presumed to be identical,
recovery after splenic shielding was “seeding of hema- based on their appearance and blood types.17 Both
topoietic elements to various organs,” then “seeding of these transplants led to successful marrow recovery
with the cellular constituents of bone marrow, as by within 2 weeks after lethal dose of TBI. Posttransplant
intravenous injection, should also be effective in has- BM biopsy showed complete remission of their leuke-
tening recovery.”6 Soon, multiple studies investigated mia, though leukemia relapsed in both children within
the role of BM infusion in mice, dogs, and monkeys 2–3 months. From these cases, it was learned that more
with leukemia treated with lethal doses of TBI.7–16 intense conditioning was needed in addition to TBI
Hematopoietic Cell Transplantation for Malignant Conditions. https://doi.org/10.1016/B978-0-323-56802-9.00001-8
Copyright © 2019 Elsevier Inc. All rights reserved. 1
2 SECTION I History and Basic Science of Hematopoietic Cell Transplantation

to prevent malignant disease relapse in patients who included cadavers, twins, siblings, other family mem-
receive immunologically identical grafts. bers, or some other random donor. Some cases received
In 1965 Mathe et al. summarized results of 14 allo- BMs from multiple donors. Also, with no knowledge
geneic BMTs after lethal-dose TBI.18 This series provided of human leukocyte antigen (HLA) typing, procedures
detailed description of the “secondary syndrome” after for most of these cases were carried out without any
transplant, an entity later recognized as graft-versus- matching; in some cases ABO-matched donors were
host disease (GVHD) and its treatment with steroids. used, and only 3 of 203 transplants performed in the
In addition, the clinical use of donor lymphocyte infu- later period used an “HLA-matched” donor when the
sion (DLI) and its incitement of GVHD was described awareness of HLA began to surface.
for the first time. Some of these patients died of aplasia
without engraftment; some had temporary engraftment The Significance of HLA Matching in
with no “secondary syndrome”; some patients had per- Transplant
sistent engraftment for up to 3 months, whereas oth- Some of the pioneers in the discovery of Major Human
ers had complete engraftment, but died of “secondary Histocompatibility Complex were Jean Dausset and
syndrome.” One long-term survivor after transplant J.J. van Rood who described the existence of leukocyte
was a 26-year-old physician with refractory acute lym- antibodies in late 1950s.20,21 Dausset detected allore-
phoblastic leukemia (ALL). He was conditioned with active antibodies in the serum of a leukopenic patient
6-mercaptopurine and TBI, followed a week later by who had received multiple blood transfusions, which
infusion of pooled BM obtained from 6 related donors were able to bind leukocytes of another individual. This
(father, mother, 3 brothers, and 1 sister). Recovery of led him to believe that human leukocyte groups simi-
neutrophils and platelets occurred around day 15 and lar to the ABO group existed, but antibodies against
day 28, respectively. About a week after transplant, he them appeared only after immunization in contrast to
developed “secondary syndrome” manifesting as severe the naturally existing ABO antibodies. In subsequent
diarrhea, vomiting, 15-kg weight loss, generalized skin experiments, he realized that alloimmune antibodies
desquamation, hepatosplenomegaly, and transamini- reacted against almost half of the volunteer donors,
tis. He was treated with steroids, which led to improve- suggesting that the same leukocyte groups were pres-
ment after 2 months. He was noted to have engrafted ent in those individuals, which he called “MAC” (acro-
from one of his brothers, based on the RBC phenotype. nym of initials of the first three donors whose serum
In addition, he received skin grafts from all six donors, did not react). He then tested sera from 50 different
which he rejected except for the graft from the same individuals and established the existence of at least 8
brother whose RBCs were circulating in the recipient. leukocyte groups presumably related to a single genetic
About 6 months after transplantation, he was given system, which he named as Hu-1 (“Hu” for human
four-weekly DLIs from the same donor, after which the and “1” for the first system). This was shown to cor-
“secondary syndrome” reappeared which was again relate with the fate of skin and kidney grafts. The Hu-1
successfully treated with steroids. He was alive in remis- was later renamed as Human Leukocyte Antigen. Jean
sion at 1 year after transplantation.18 Dausset was awarded the Nobel Prize of Medicine in
Although there were occasional success stories and 1980 for his discovery. Further experiments by J.J van
vigorous interest in BMT until early 1960s, the enthusi- Rood22 and Rose Payne23 established the presence of
asm withered due to extremely poor outcomes.19 This distinct antigenic and allelic groups in the population.
was elegantly summarized by Bortin in a compendium Experiments by Bach and Amos in 196724 suggested
of 203 allogeneic transplants performed between 1939 that major histocompatibility antigens in humans were
and 1969,19 of which 75% were performed before controlled by single genetic locus (HLA) at which mul-
1962. No engraftment was observed in 62% (125/203), tiple alleles may operate.
and the overall mortality was about 75% (152/203). The significance of HLA matching in animal mod-
The indications for BMT were acute leukemia (42%), els of BMT was identified in the early 1950s. In 1953
aplastic anemia (36%), other malignant disorder Snell demonstrated the role of mouse histocompat-
(15%), or immune deficiency (7%). Many of these ibility genes, especially H-2, in transplantation.25 In
transplants were performed without any conditioning; 1957 Uphoff showed that transplantation of either
some used steroids alone, others used TBI, and some parental or allogeneic marrow that differed at the H2
received chemotherapy with 6–MP or cyclophospha- locus caused death of F1 hybrid mice due to the “reac-
mide ± other agents. In the absence of any understand- tions caused by graft against the host” and noticed that
ing of GVHD, no prophylaxis was used. Donor sources this syndrome could be evaded if the donor and the
 CHAPTER 1 History and Current Status of Hematopoietic Cell Transplantation 3

recipient were H-2 identical.26 Later, similar findings In 1977, E.D. Thomas reported a series of 100 consec-
were noted by others in dogs.27–29 Soon, a series of utive patients with acute leukemia (acute myelogenous
experiments conducted by E.D. Thomas’ group in late leukemia [AML], n = 54, and ALL, n = 46) who underwent
1960s through early 1970s revealed that lethally irra- BMT between 1971 and 1975 from their HLA identical
diated dogs that received marrow from dog leukocyte siblings.44 After treating first 10 patients with TBI alone,
antigen–matched dogs, especially those who received it was recognized that further intensive conditioning was
methotrexate, had long-term survival as compared with needed to reduce the risk of recurrent leukemia. Subse-
those who received graft from DLA-mismatched dogs quently, chemotherapies such as cyclophosphamide,
who died of graft rejection or GVHD.27,30,31 Thereafter, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and/or
BMTs using HLA-matched donors began in humans. others were added to TBI. All patients received metho-
trexate for prevention of GVHD, at a dose of 15 mg/
Late 1960s: The First Successful m2 on day 1, followed by 10 mg/m2 on days 3, 6, and
HLA-Matched Sibling BMTs 11 and weekly thereafter for first 100 days (known as
HLA testing in that era was performed using serological long-course methotrexate). About 75% of the patients
methods which detected antibodies in human serum developed GVHD, which was often treated with antithy-
that were capable of agglutinating human periph- mocyte globulin (ATG). Only 1 patient rejected the graft;
eral blood (PB) T cells (HLA class I) or B cells (HLA six patients died before engraftment while all others (94
class II), using techniques such as the mixed leukocyte of 100) engrafted. Overall, 55 patients died before day
reaction (MLR) and lymphocyte typing,24,32,33 lym- 100 due to GVHD, interstitial pneumonia, recurrent leu-
phocytotoxic approach,34 or the complement fixation kemia, or other medical complications. Long-term sur-
technique.35 Using these methods, the first cases of suc- vival of up to 9 years45 seen in some of these refractory
cessful HLA-matched sibling BMTs in pediatric patients end-stage leukemia patients suggested that BMT should
with nonmalignant disorders were reported in 1968 be considered early during their disease trajectory.
in the same issue of Lancet. One of these, performed Subsequently, Thomas and his collaborators started
at the University of Minnesota36 involved a 5-month- performing transplants in patients with AML in first
old male who had sex-linked lymphopenic immuno- remission. In 1979 they reported outcomes of 19 such
logical deficiency, who received PB buffy coat and BM patients who underwent HLA-matched sibling BMT
from HLA-matched sibling, which restored cellular after a preparative regimen of intrathecal methotrexate,
and humoral immunity. The other one37 performed at cyclophosphamide, and high-dose TBI.45 All patients
the University Hospitals, Madison, involved a 2-year- received GVHD prophylaxis with the long course of
old boy with Wiskott-Aldrich syndrome, who received methotrexate as described. Only 1 patient relapsed, and
azathioprine and prednisone before BMT, which was 12 of the 19 (63%) patients survived. In the same year
unsuccessful. Thereafter, he received an infusion of PB the group from City of Hope Medical Center reported
leukocytes from the same donor, followed by adminis- significantly improved survival after HLA-matched sib-
tration of high-dose cyclophosphamide and then BMT ling BMT in “good-risk” AML patients in first remission
from the same donor. The patient became transfusion (n = 26) as compared to a control group (n = 21) who
independent, and his spleen size normalized. This case did not undergo BMT because they had no donor.46
highlighted the importance of eliminating recipient’s Soon several reports described cure of diseases with
alloreactive immune cells (incited by donor PB cells BMT that were considered incurable with traditional
and then eradicated with cyclophosphamide) to allow therapies, including chronic leukemia,47–51 thalas-
engraftment. semia,52,53 and sickle cell anemia.54

Interest in BMT Re-Emerged in 1970s and Late 1970s to Mid-1980s: Use of Unrelated
Transplants Were Tested in Earlier Stage Donors
Malignant Disease With the success with HLA-matched sibling BMT, the
As it was becoming clear that treating animals donor selection was expanded to HLA-matched unre-
with methotrexate not only improved engraftment lated donors (MUDs) for those who lacked sibling
but also survival by limiting their “secondary syn- donors. The first successful MUD HCT was performed
drome,”27,30,31,38–43 the concept of GVHD prophylaxis in 1973 at the Westminster Hospital, London, on a
was clinically introduced in the 1970s. This, along with boy named Simon Bostic who was born with X-linked
increasing knowledge of HLA matching, reignited the chronic granulomatous disorder (CGD).55,56 He had
interest and clinical activity in BMT. no HLA-matched family donor, and prior cases of
4 SECTION I History and Basic Science of Hematopoietic Cell Transplantation

A B
FIG. 1.1 (A) Simon Bostic with parents Elizabeth and Roger. (B) Simon Bostic at Victoria Falls in Zambia
during a Comic Relief 2013 celebrity Zambezi challenge. ((A and B) Courtesy of the Daily Mirror.)

MUD transplant in other diseases had been unsuccess- engraftment due to multiple prior blood transfusions
ful.57 However, as his elder brother, who also had CGD, and potential alloimmunizations. Since then, with the
died at the age of 2 years, his family agreed to pursue establishment of the National Marrow Donor Program
MUD HCT. Simon’s mother commenced determined (NMDP) in the United States and the Anthony Nolan
campaigning to look for unrelated donors, starting Donor Registry in the UK and progressively easier
with getting her friends tested. The story got published access to search for donors, the numbers of MUD HCTs
in local and national press and soon numerous people increased rapidly and surpassed the numbers of HLA-
from several continents got their blood tested. Eventu- matched sibling HCTs after mid-late 2000s, both in
ally, a 29-year-old female was found to be a match at the United States (Fig. 1.2) and in Europe. In Europe,
HLA-A, HLA-B, and HLA-D loci. At the age of almost MUD HCT constituted 53% of all allogeneic HCTs in
2 years, Simon received MUD BMT after conditioning 2014 and represented an 80% increase over the past
with cyclophosphamide (60 mg/kg). He had mixed chi- 15 years.62,63
merism after transplant but later completely lost donor
cells by the age of 7 years. They refused the idea of sec- 1980−90: Use of PB as Autograft
ond transplant, and he struggled with recurrent infec- The recognition of hematopoietic progenitor cells
tions while on chronic antibiotics but was reported in PB of mice, dogs, and nonhuman primates has
alive for over 40 years (Fig. 1.1).58 been recognized since the 1960s,7,64,65 followed by
The first HLA-MUD BMT for a malignant condition attempts to harvest these from circulation in man.
was performed at the Fred Hutchinson Cancer Research One of the ground-breaking steps toward this goal
Center on September 4, 1979, in a 10-year-old girl with was the development of closed system continuous-
ALL in second remission who had no HLA-identical flow apheresis technology, which was first developed
sibling. However, based on the published population in 1960s by a collaborative effort of the National Can-
HLA analysis,59 she was noted to have inherited two cer Institute and the International Business Machines
relatively common HLA haplotypes. Therefore five nor- Corporation (NCI-IBM).66,67 A decade later, this was
mal donors were randomly screened, and one of them put to clinical testing at the M.D. Anderson Cancer
was noted to be ABO, HLA-A, HLA-B, HLA-D (MLR typ- Center.68 Another decade passed before the feasibil-
ing), and DR matched with the patient. She received ity of collecting large quantities of PB progenitor cells
BMT after conditioning with methotrexate, cyclophos- (PBPCs) from adult volunteers was demonstrated by
phamide, and TBI, followed by long-course methotrex- Körbling M et al.69
ate for GVHD prophylaxis. She was reported to be well The finding that autologous PB could be used for
at least until 10 months after transplantation without successful marrow recovery in man was first shown by
GVHD.60 Goldman et al. in 1979 in a patient with chronic phase
Shortly afterward, two successful cases of MUD CML by using cryopreserved buffy coat cells70,71 and
BMTs were reported in 1982 in patients with aplas- again by Korbling et al.72 in 1981 using cryopreserved
tic anemia,61 a disease which offers challenges for PBPCs obtained by leukaphereses. The follow-up
 CHAPTER 1 History and Current Status of Hematopoietic Cell Transplantation 5

FIG. 1.2 Numbers of allogeneic HCTs performed in the United States by donor type since 1980s. HCT,
hematopoietic cell transplantation; URD-BM/PB, Unrelated donor bone marrow/peripheral blood; UCB,
Umbilical cord blood.

period in these studies was too short to draw any clini- received PBPC (7.1 × 1010 total nucleated cells [TNCs]
cal conclusions about its use. It took another 5 years containing 3.4 × 104 myeloid progenitors colony-
before long-term safety and efficacy of PB HCT could forming unit cell (CFU–C)/kg) obtained by leukaphere-
be established. In 1986 Korbling et al.73 demonstrated sis from an identical-twin. After no marrow recovery by
sustained engraftment and marrow cellularity for 2 months, he received a BM graft from the same donor
>7 months after autologous PB HCT in a patient with that contained significantly fewer cells (1.3 × 1010 TNCs)
Burkitt’s lymphoma. Leukaphereses and collection of but almost double the numbers of myeloid progeni-
PBPCs were done after COMP (cyclophosphamide, vin- tors (6.4 × 104 CFU-C/kg), which resulted in prompt
cristine, methotrexate, and prednisone) chemotherapy. marrow recovery.81 Then in 1980 Abrams et al.82
The patient was reportedly alive and well 25 years after described a case of a patient with Ewing’s sarcoma who
transplantation.74 received PBPCs from identical twin by leukapheresis
The use of granulocyte colony–stimulating factor (9.8 × 1010 TNCs containing 40 × 104 CFU-C), which did
(G-CSF) or granulocyte macrophage colony–stimulating not support either neutrophil or platelet engraftment.
factor for collection was introduced in late 1980s and Subsequent infusion of autologous BM restored blood
early 1990s, with several reports of successful autolo- counts.
gous PB HCT.73,75–79 Since then, the number of autolo- It took another decade before PBPCs were rein-
gous HCTs has been constantly increasing, especially in troduced in the allogeneic setting. In 1989 Kessinger
older patients, including those over the age of 70 years et al.83 from the University of Nebraska reported a case
(Fig. 1.3).62,63 of HLA-matched sibling donor PB HCT in an 18-year-
old male with ALL whose sibling preferred to donate
Early 1990s: Rapid Increase in Allogeneic PB than BM. Although the patient engrafted neutro-
Transplantation Using PB Grafts phils on day 11 and achieved 100% engraftment from
The notion of using PBPC in the allogeneic setting was donor cells, he unfortunately died on day 32 after
initially faced with resistance in the 1970s-1980s due transplant from disseminated aspergillosis, likely due
to concerns about their lower self-renewal potential,80 to T cell depletion from the graft which was performed
which was emphasized after 2 reports of failed syngeneic to reduce the risk of GVHD. The first successful G-CSF–
donor PB HCTs.81,82 In 1979, Hershko et al.81 reported mobilized PB HCT was reported in 1993 by Dreger
a case of paroxysmal nocturnal hemoglobinuria, who et al.84 from the University of Kiel, in a 47-year-old
6 SECTION I History and Basic Science of Hematopoietic Cell Transplantation

FIG. 1.3 Trend of autologous HCT performed in the United States since 2000 by age. HCT, hematopoietic
cell transplantation.

female with AML using HLA-matched sibling after two 1970s,90–92 but the results were discouraging due to
prior failed BMTs from the same donor. A few months high rates of GVHD, graft failure, and excessive risk
later, Russell et al.85 reported a PB HCT in 45-year-old of toxicities including pulmonary injury and multi-
male with ALL using an HLA-matched sibling donor. organ failure.93,94 For instance, in a study reported
In the early 1990s there was steep growth in allo- in 1985 by Beatty et al.,93 the risk of graft rejection
geneic G-CSF (filgrastim) mobilized PB HCT, after tri- and grade II-IV acute GVHD was significantly higher
als led by M.D. Anderson Cancer Center,86 University (70% vs. 42%, P < .001) after myeloablative haploi-
of Kiel, Germany,87 and the Fred Hutchinson Cancer dentical HCT (n = 105) than HLA-matched sibling
Research Center88 established the safety and efficacy BMT (n = 728).
of PB HCT in patients with relapsed/refractory hema- As the role of T cells in the pathogenesis of GVHD
tologic malignancies. However, concerns also began to became apparent,95–99 several cases of T cell–depleted
emerge about potentially higher risks of GVHD than haploidentical transplant were reported in early
BMT.88 This was resolved more than a decade and a half 1980s,100–102 with <5 × 104 CD3 cells/kg recognized as
later in numerous randomized trials comparing BM the safe threshold for preventing GVHD.103 Although
versus PB grafts, most of which showed significantly T cell depletion seemed effective in patients with severe
higher risks of chronic GVHD with PB HCT.89 Despite combined immunodeficiency, it did not prevent disease
this, PB remains the most commonly used graft source relapse or graft failure/rejection in patients with acute
(75%–80%) for adult patients undergoing either HLA- leukemia.104,105 The risk of graft failure/rejection was
sibling (Fig. 1.4A) or unrelated donor (Fig. 1.4B) noted to be 50% in recipients of T cell–depleted HLA-
HCT, in the United States and in Europe.62,63 No clear mismatched grafts in contrast to only 10% in recipients
data suggest the scientific rationale for this dependence of T cell–depleted HLA identical graft and 1% or less in
on PBPC grafts for adults. In contrast, PB is the not recipients of unmodified BM grafts from HLA identical
preferred as a graft source (about 20%) for pediatric donors.100 Graft failure occurred due to the emergence
recipients of either HLA sibling (Fig. 1.4C) or unrelated of host-derived T cells even after patients had received
donor (Fig. 1.4D) HCT.62 conditioning with myeloablative TBI, cyclophospha-
mide, and in some cases, ATG.106,107
Haploidentical Stem Cell Transplantation The concept of infusing massive doses of progenitor
The possibility of using related donors other than cells, which in preclinical studies was shown to overcome
HLA identical siblings was explored in the late the HLA barrier,108,109 was explored by the Perugia group
 CHAPTER 1 History and Current Status of Hematopoietic Cell Transplantation 7

FIG. 1.4 (A) Trend of sibling donor HCT in patients older than 18 years by graft source in the United
States. (B) Trend of MUD HCT in patients older than 18 years by graft source in the United States. (C) Trend
of sibling donor HCT in patients younger than 18 years by graft source in the United States. (D) Trend of
MUD HCT in patients younger than 18 years by graft source in the United States. BM, bone marrow; HCT,
hematopoietic cell transplantation; PB, peripheral blood.

in the 1990s. They performed T cell–depleted transplants Other strategies attempted to balance the risk
with grafts containing “mega doses” of hematopoietic of GVHD and disease relapse after haploidentical
cells obtained from BM plus G-CSF–mobilized PB.110 HCT included partial T cell depletion using combi-
The final graft contained >10.8 × 106 CD34 cells/kg and nation of in vivo and ex vivo monoclonal antibod-
a median of 2 × 105 CD3 cells/kg. Intensive conditioning ies or immunotoxin,112,113 in vivo T cell depletion
with TBI, cyclophosphamide, thiotepa, and ATG provided with the anti-CD52 monoclonal antibody alemtu-
both immunosuppression and myeloablation. With no zumab,114,115 or ATG.116 More recently, the field has
further GVHD prophylaxis, only 18% of the patients reverted back to using T-cell replete grafts using
developed acute GVHD. In their subsequent study,111 even novel GVHD prophylaxis regimens such as post-
more intense T cell depletion was performed, resulting in transplant cyclophosphamide117 or selective αβ + T
one-tenth the dose of CD3+ cells as compared to the prior cell–depleted grafts.118,119 With these novel strat-
study, and cyclophosphamide was replaced with fludara- egies, the outcomes of haploidentical HCT have
bine. This completely abrogated the risk of graft failure improved remarkably and now approach those of
and prevented both acute and chronic GVHD, but almost MUD HCT.120,121 As a result, the numbers of hap-
half of the patients with ALL relapsed. loidentical HCT are increasing steadily both in the
8 SECTION I History and Basic Science of Hematopoietic Cell Transplantation

United States (Fig. 1.2) and in Europe,62,63 with PB effort between investigators at the Rockefeller Univer-
grafts being used more frequently than BM (Fig. 1.5). sity (A.D. Auerbach), Indiana University (H.E. Brox-
meyer), Memorial Sloan Kettering Cancer Center (E.A.
History of Umbilical Cord Blood Transplant Boyse), Duke University Medical Center (J. Kurtzberg),
Among all donor/graft sources, the field of umbilical and Hôpital Saint Louis, Paris (E. Gluckman). Auer-
cord blood transplant (UCBT) is the most juvenile, bach et al. developed a method of prenatal diagnosis
although the notion is ancient. The potential of using of FA by chorionic villous and amniotic fluid sam-
fetal or newborn progenitor cells as a graft source was pling in fetuses at risk and simultaneously performed
first observed in the 1950s when studies in lethally HLA typing to determine if they would be HLA identi-
irradiated mice showed that liver/spleen hematopoi- cal to the affected sibling.128 If they tested negative,
etic cells from newborns provided longer term survival UCB was harvested at the time of birth, which was
than adult marrow cells.122 Fetal liver as a graft source found to be a rich source of progenitor cells. Further
was investigated in animals in late 1950s123,124 and studies by Broxmeyer et al.129 showed that human
shortly thereafter in humans by Scott et al.,125 but the UCB contained multipotent colony-forming units
outcomes were disappointing.125 Logistical difficulties (CFU-GEMM), erythroid burst-forming units, and
in obtaining the graft and success of HCTs with BM granulocyte-macrophage (CFU-GM) progenitor cells,
or PB grafts further limited interest in the cord blood in frequencies similar or greater than that in adult
approach. marrow and sufficient to allow marrow recovery128,129
In early 1980s it was shown that samples from new- based on reported cell doses from BMTs. This was
born umbilical cord blood (UCB) contained hemo- confirmed in lethally irradiated mice by Boyse in an
poietic colony-forming cells which could be grown unpublished work.129
in liquid suspension culture for over 3 months and This extensive preclinical work led to the first UCBT
provided the best enrichment of immature myeloid which was performed on October 6, 1988, in a 5-year-
cells in vitro as compared to adult BM or PB.126,127 old boy with FA named Matthew Farrow.130 This was
These findings ignited the interest in using UCB as a combined effort of the investigators mentioned pre-
a graft source. The clinical translation of these find- viously, but the transplant was conducted at Hôpital
ings rooted from research in Fanconi anemia (FA) Saint Louis under the supervision of E. Gluckman due
and was a result of multi-institutional collaborative to her expertise in managing these patients.131 Matthew

FIG. 1.5 Trend of haploidentical HCT in the United States over time by graft source. HCT, hematopoietic
cell transplantation.
 CHAPTER 1 History and Current Status of Hematopoietic Cell Transplantation 9

was diagnosed with FA at the Duke University Medical The applicability of UCBT was soon extended to
Center at the age of 2 years. When his mother became several malignant and nonmalignant disorders using
pregnant again, prenatal testing at the Rockefeller Uni- matched133–136 or partially matched137 sibling donors
versity revealed the female fetus not only to be unaf- and later from mismatched unrelated donors as
fected by FA but also 6/6-HLA match to him. Matthew’s well.137–139 Common findings from these studies were
physician, Joanne Kurtzberg, proposed UCBT from his delayed neutrophil engraftment, lower risks of GVHD,
yet-to-be-born sister. Cord blood was collected and and comparable survival with UCBT compared with
cryopreserved at birth and hand delivered from Indi- BMT. By early-mid 1990s, the field expanded to include
ana to Paris when he was admitted for transplant. He adult patients.138,140 But the cell dose in a single UCB
received reduced intensity conditioning (RIC) with unit was soon recognized to be inadequate for many
low-dose cyclophosphamide (20 mg/kg) and 5 Gy adults. This was addressed by Barker et al. at the Univer-
thoraco-abdominal irradiation, a regimen previously sity of Minnesota who pioneered the use of double unit
shown by Gluckman to be effective and safe in FA UCBT,141 which has now become a standard in those
patients.132 Cord blood cells were thawed and infused with insufficient cell dose in a single unit. Later, mul-
without further processing at a dose of 0.4 × 108 TNCs/ tiple novel ex vivo graft manipulation techniques were
kg. GVHD prophylaxis constituted of cyclosporine introduced to increase the progenitor cell dose and
from day 1 through 6 months after transplantation. accelerate engraftment, leading to improved outcomes
On day 15, he developed histological grade 1 skin (reviewed in the studies of Mehta et al.142–144).
GVHD and hepatic GVHD, which was successfully Other major landmarks in the history of UCBT
treated with steroids. Signs of engraftment appeared were the establishment of several UCB banks after
on day 22. He required blood and platelet transfu- the first unrelated UCB bank was created in 1991 by
sions until day 54 and 43, respectively, after which Rubinstein at the New York Blood Center.145–147 With
he became transfusion independent. Day 120 BM a large inventory of UCB banks and the establishment
analysis showed 100% cells of donor origin (46, XX), of several registries (see section “Origin of Donor and
but he had mixed chimerism in the PB (64% donor) Transplant Registries”), the numbers of UCBT in the
through 204 days after transplantation. He is doing United States increased steadily from 2003 to 2011
well without any GVHD more than 33 years after the but are now slowly declining as the number of hap-
transplant (Fig. 1.6).130,131 loidentical HCTs surpassed that of UCBTs in 2014.

A B
FIG. 1.6 (A) Matthew Farrow, age 5 years, 1988. (B) Recent photograph of Matthew Farrow—now a hus-
band and a father. ((A) Courtesy: www.bmtinfonet.org. (B) Courtesy: photo by fellow transplantee Rodney
Curtis/RodneyCurtis.com and www.bmtinfonet.org with permission from Matthew Farrow.)
10 SECTION I History and Basic Science of Hematopoietic Cell Transplantation

In pediatrics, UCBT constituted about half (48%) (8 mg/kg),161 melphalan,163 thiotepa,164 and cyclo-
of all unrelated donor grafts in 2009 but declined phosphamide164–166 with or without low-dose TBI
thereafter and were about one-third of all MUDs in (generally 200 cGy).165–168 The risk of toxicities in
2015. In adults the number of UCBTs plateaued since these studies was noted to be significantly lower
2010 and accounted for less than 10% of all MUDs than that reported with conventional myeloablative
in 2015 (Fig. 1.4B and D).62 Similarly, in Europe, in regimens.
recent years (2011–14), the number of UCBT dropped With the advent of NMA/RIC regimens, the number
slightly as haploidentical HCT have increased by 25% of patients aged 60–70 years or older undergoing HCT
annually.63 steadily increased (Fig. 1.7). In 2015, 30% of the allo-
geneic HCTs performed in the United Staes included
Late 1990s to Early 2000s: Introduction of patients older than 60 years.62
RIC
Until the 1980s, the success of HCT relied on myeloab- Origin of Donor and Transplant Registries
lative conditioning with high-dose TBI (10–15 Gy) After the first successful MUD HCT was performed
with or without cyclophosphamide (120–200 mg/kg) in 1973, this news reached Australia and to Shir-
or other chemotherapies and later with high-dose oral ley Nolan, whose 2-year-old child, Anthony Nolan,
busulfan (16 mg/kg)148 as an alternative to TBI. As there was born with Wiskott-Aldrich syndrome and had
is a positive dose-response correlation of most hemato- no available HLA-matched donor. She came to the
logical malignancies to alkylating agents and radiation, UK with hopes that Simon’s doctors could also save
it made sense to administer exceptionally high doses Anthony.58 With an idea to start a BM registry to search
of chemotherapy and/or radiation to eradicate tumors for potential unrelated donors, she started campaign-
before transplant. ing and fundraising which led to the establishment of
The existence of graft-versus-tumor effect was the world’s first marrow donor registry, the Anthony
recognized in late 1950s in murine models by Nolan Bone Marrow Registry in 1974 in Westmin-
Barnes et al. who noted that allogeneic, but not ster Children’s Hospital, where Anthony was being
syngeneic, marrow infusion into irradiated mice treated (Fig. 1.8). Although it could not help Anthony,
resulted in eradication of leukemia.12,149 But it who died in 1979, the registry continued to expand
was not until the late 1970s and early 1980s, and currently includes 600,000 potential donors. In
when the graft-versus-leukemia (GVL) effect was 1988 it became a founding member of Bone Marrow
observed in human studies that demonstrated sig- Donors Worldwide (BMDW), and in 2008 it estab-
nificantly lesser risk of leukemia relapse in patients lished the UK’s first dedicated UCB bank (https://www.
who developed GVHD than those without.150–153 anthonynolan.org/).
In addition, there was an increased risk of relapse In the United States, Dr. Mortimer M. Bortin and
with T cell depletion150 and induction of remission several colleagues established the International Bone
after DLIs.154 These all further provided evidence Marrow Transplant Registry (IBMTR) at the Medical
for GVL effect of HCT. Thus, it was hypothesized College of Wisconsin in 1972 to gather patient data
that the power of HCT could be harnessed without and analyze their outcomes. In 1986 a national regis-
myeloablation. try of unrelated volunteer donors, the National Bone
One of the earliest attempts to reduce toxicities Marrow Donor Registry (later renamed as National
was to reduce the doses of chemotherapies.155–157 Marrow Donor Program, NMDP) was established
However, it was also noted that adequate immuno- in St. Paul, MN, as a joint effort of the Graves’ fam-
suppression was critical to prevent graft rejection ily (whose 10-year-old daughter with leukemia was
mediated by recipient T cells.106,107 With preclinical saved by a MUD HCT), other patient families, doc-
data suggesting that fludarabine plus TBI yielded tors, US Congressional support, and funding from
sufficient immunosuppression as achieved with TBI the US Navy (https://bethematch.org). In July 2004,
plus cyclophosphamide, but with fewer toxicities,158 the IBMTR and NMDP collaboratively formed the
fludarabine was included in conditioning regimens Center for International Blood and Marrow Trans-
in the mid-late 1990s.111,158–162 This opened the plant Research (CIBMTR) with a mission to improve
opportunities for development of a wide variety of transplantation access and outcomes for patients.
nonmyeloablative (NMA) and RIC regimens with The CIBMTR has been collecting outcomes data on
various combinations of fludarabine plus reduced nearly all allogeneic transplantations performed in
doses of alkylating agents such as low-dose busulfan the United States for over 40 years and has data on
 CHAPTER 1 History and Current Status of Hematopoietic Cell Transplantation 11

FIG. 1.7 Trends in allogeneic HCT in the United States over time, by age group. HCT, hematopoietic cell
transplantation.

more than 465,000 patients (https://www.cibmtr.

org/). It also receives voluntary data on autologous
transplants and some allogeneic HCTs performed
internationally. With similar goals, transplant teams
from Paris, Leiden, London, and Basel started meet-
ing since 1975, which in 1979 ultimately led to the
formal establishment of the European Society for
Blood and Marrow Transplantation in the Nether-
lands (https://www.ebmt.org/).
The idea of World Marrow Donor Association
(WMDA) was initiated in 1988 to identify donors in
an international collaboration by three pioneers—E.
Donnall Thomas (US), John Goldman (UK), and J.J.
van Rood (NL). Foundation of the WMDA was for-
mally established in 1994, and in January 2017 BMDW
joined the WMDA. Its goal is to facilitate exchange of
high-quality progenitor cells for patients worldwide
and to promote the interests of donors. It currently
represents 75 donor registries, 158 cord blood banks,
350 donor centers, and 1615 transplant hospitals from
52 different countries (https://www.wmda.info/).
Likewise, to improve outcomes of UCBT, international
registries were formed such as the Eurocord in 1995 (http FIG. 1.8 Shirley Nolan with Anthony. (Courtesy of the
://www.eurocord.org/) to collect UCBT outcome data and Daily Mirror.)
NetCord in 1998 (http://www.netcord.org/) to establish
12 SECTION I History and Basic Science of Hematopoietic Cell Transplantation

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