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CHAPTER 23 HISTORY

HEMATOPOIETIC CELL The successful clinical application of hematopoietic cell transplan-
tation (HCT) required a century of key developmental discoveries
TRANSPLANTATION (Table 23–1). Between 1868 and 1906, European and American inves-
tigators established that marrow cells were the source of blood cell pro-
duction. In 1939, the first documented human marrow transplant was
performed in a patient with gold-induced marrow aplasia. The patient
1
Andrew R. Rezvani, Robert Lowsky, and Robert S. Negrin was infused intravenously with marrow from a brother with an identical
ABO blood type. The transplant was not successful, and the patient died
5 days after the marrow infusion.
In 1922, a Danish investigator modified radiation injury in guinea
SUMMARY pigs by shielding their femora against radiation, preventing the typi-
cal radiation-induced thrombocytopenia and hemorrhage. This work
2
Over the past 60 years, the field of hematopoietic cell transplantation (HCT) went essentially unnoticed for more than 2 decades. The period of 1949
has evolved from experimental animal models of marrow transplantation to to 1954 was marked by a political climate concerned with the threat of
curative therapy for tens of thousands of people yearly who are affected by continued atomic warfare, which stimulated support for experiments
a wide variety of marrow failure states, myeloid and lymphoid malignancies, studying the effects of irradiation and led to the development of the field
immune deficiencies, and inborn errors of metabolism. Advances in transplan- of organ and marrow transplantation. Jacobson and colleagues found
tation immune biology combined with improvements in supportive care have that mice could survive an otherwise lethal irradiation exposure if the
3
made this evolution possible and have ushered in the modern era of HCT. This spleen (a hematopoietic organ in the mouse) was protected by lead foil.
chapter discusses the biologic principles and clinical applications of HCT along Soon afterward, Lorenz and colleagues showed that lethally irradiated
mice and guinea pigs were protected by the administration of synge-
with its future applications. Selected results demonstrating important princi- neic marrow after irradiation, thereby demonstrating the therapeu-
ples are highlighted. tic efficacy of allogeneic and xenogeneic marrow suspensions. These
4
investigators and others considered that chemicals and/or components
from the shielded spleen or infused marrow stimulated endogenous
hematopoietic cell recovery after total-body irradiation (TBI). In
5–7
Acronyms and Abbreviations: ALL, acute lymphoblastic leukemia; ALK+, 1954, Barnes and Loutit showed that if mice were immunized against
anaplastic lymphoma kinase–positive; AML, acute myeloid leukemia; APC, antigen- marrow cells from mice of another strain and then lethally irradiated,
presenting cells; ASBMT, American Society for Blood & Marrow Transplantation; ATG, no protection was observed by the injection of marrow cells from the
antithymocyte globulin; BCNU, 1,3-bis(2-choloroethyl)-1-nitrosurea; BEAM, BCNU, strain to which they were immunized. However, if nonimmunized mice
etoposide, cytarabine, and melphalan; BMT-CTN, Blood & Marrow Transplant Clinical were lethally irradiated and injected with the same marrow cells, nor-
Trials Network; BU, busulfan; CIBMTR, Center for International Blood and Marrow mal protection was seen and all mice survived more than 60 days. This
Transplant Research; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous experiment supported the cellular hypothesis of hematopoiesis and was
leukemia; CMV, cytomegalovirus; CR, complete remission; CR1, first complete remis- the first to consider that hematopoietic recovery resulted from cellular
sion; CT, computed tomography; CXCL12, extracellular-matrix-bound stromal cell– repopulation and not from humoral factors. 8
derived factor-1; CXCR4, chemokine-related receptor 4; CY, cyclophosphamide; DAH, In 1956, Barnes and associates described the treatment of murine
9
diffuse alveolar hemorrhage; DLI, donor lymphocyte infusion; EBMT, European Soci- leukemia by supralethal irradiation and marrow grafting. Researchers
ety for Blood and Marrow Transplantation; ECP, extracorporeal photopheresis; FDG, pointed out that irradiation alone would not kill all leukemia cells, but
18-fluorodeoxyglucose; FLU, fludarabine; G-CSF, granulocyte colony-stimulating fac- that residual leukemia cells might be eliminated by transplanted cells
tor; GI, gastrointestinal; GM-CSF, granulocyte-monocyte colony-stimulating factor; through immunologic mechanisms, and the term adoptive immune
GVHD, graft-versus-host disease; GVT, graft-versus-tumor; HCT, hematopoietic cell therapy was coined. Their publication stimulated tremendous interest,
transplantation; HCT-CI, HCT-specific Comorbidity Index; HL, Hodgkin lymphoma; and the period from 1956 to 1959 was characterized by an increasing
HLA, human leukocyte antigen; HSC, hematopoietic stem cell; HSV, herpes simplex appreciation of the potential application of marrow grafting to treat
virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IPS, idiopathic pneumonia individuals exposed to lethal irradiation and to treat human leukemia.
syndrome; KTLS, c-kit , Thy-1.1 , lineage marker , and Sca-1 ; MDS, myelodysplas- Thomas and colleagues began clinical studies in patients with terminal
–/lo
lo
+
+
tic syndrome; MHC, major histocompatibility complex; MMF, mycophenolate mofetil; leukemias, and in 1957 described six patients treated with irradiation
10
MSC, mesenchymal stromal cell; MTX, methotrexate; NHL, non-Hodgkin lymphoma; and intravenous infusion of marrow from healthy donors. Only two
NIH, National Institutes of Health; NK, natural killer; NMDP, National Marrow Donor patients developed transient detectable donor hematopoietic engraft-
Program; PAM, Pretransplant Assessment of Mortality; PBPC, peripheral blood pro- ment, and none of the six survived beyond 100 days from the cell infu-
genitor cell; PCA, patient-controlled anesthesia; PCR, polymerase chain reaction; sion. In 1959, Thomas and associates described a patient with terminal
PET, positron emission tomography; Ph, Philadelphia chromosome; PSGL-1, P-selec- leukemia who received total body irradiation (TBI) and an intrave-
11
tin glycoprotein ligand-1; PTLD, posttransplantation lymphoproliferative disorder; nous infusion of marrow from an identical twin. The patient showed
RIC, reduced-intensity conditioning; SCID, severe combined immunodeficiency; SOS, prompt hematopoietic recovery and disappearance of the leukemia for 4
sinusoidal obstruction syndrome; SRL, sirolimus; TAC, tacrolimus; TBI, total-body irra- months, confirming for the first time that lethal irradiation followed by
diation; Th, T-cell helper; TKI, tyrosine kinase inhibitor; TLI, total lymphoid irradiation; compatible marrow could have an antileukemic effect and restore nor-
TNF, tumor necrosis factor; TPN, total parenteral nutrition; T , regulatory T cell; TRM, mal marrow function. In the same year, Mathé and associates reported
reg
transplant-related mortality; UCB, umbilical cord blood; VCAM, vascular cell adhesion the infusion of marrow into six patients exposed to potentially lethal
molecule; VOD, venoocclusive disease; VZV, varicella-zoster virus. irradiation in a reactor accident in Belgrade, Serbia. Five patients
12
survived, yet there was no clear evidence of donor hematopoietic

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