McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
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Supporting Material
HEPATOBILIARY COMPLICATIONS OF HEMATOPOIETIC CELL TRANSPLANT, 40 YEARS ON
George B. McDonald, M.D.
Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center
and the Department of Medicine, University of Washington School of Medicine,
Seattle, Washington, U.S.A.
Contents:
Three figures; four appendices.
Correspondence to:
George B. McDonald, M.D.
Gastroenterology/Hepatology Section (D2 – 190)
Fred Hutchinson Cancer Research Center
1100 Fairview Avenue North
P.O. Box 19023
Seattle WA 98109 – 1024
Telephone 206 667 6932
Email gmcdonal@fhcrc.org
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
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THREE SUPPORTING FIGURES TO ACCOMPANY THESE FIGURE LEGENDS
SUPPORTING FIGURE 1. Histology of Sinusoidal Obstruction Syndrome (SOS) after
myeloablative hematopoietic cell transplant.
A.
Zone 3 of the liver acinus in an early phase of SOS, with disruption of sinusoidal
anatomy, red blood cells extending through the space of Disse, hepatocyte necrosis, and
subendothelial edema in a patent central vein (CV) (H&E).
B.
Extensive hepatocyte necrosis and dropout, disruption of sinusoids, extravasation of red
blood cells throughout zone 3, and subendothelial fibrosis (Masson trichrome).
C.
Alpha actin-positive stellate cells within zones 2 and 3 that contain areas of extensive
hepatocyte necrosis; periportal hepatocytes are intact (PV, portal vein) (alpha-smooth muscle
actin immunohistology).
D.
A later phase of SOS, showing extensive collagenization of sinusoids adjacent to two
central veins, with hepatocyte dropout and extinction of hepatocyte cords in between the veins
(Masson trichrome).
E.
Central vein and zone 3 hepatocytes later after transplant, illustrating eccentric
phlebosclerosis and collagen deposition in sinusoids (Masson trichrome).
F.
Lower power view of confluent fibrosis in and around adjacent central veins, with central
to central bridges forming a picture of “reverse” cirrhosis two months after transplant (Masson
trichrome).
(Photomicrographs by Howard M. Shulman, M.D.)
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SUPPORTING FIGURE 2. Histology of graft-vs.-host disease (GVHD) involving the liver.
A.
Portal area showing small bile ducts (arrows) with a distorted appearance, lymphocyte
infiltration, and epithelial drop-out (H&E).
B.
Small bile ducts, showing dysmorphic features, cytoplasmic eosinophilia, apoptosis
(arrow), atypical nuclei, and lymphocytic infiltration (H&E).
C.
Liver lobules from a patient with severe multisystem acute GVHD, showing fibrotic
portal spaces and periportal bile thrombi (arrows) (Masson trichrome).
D.
Immunohistochemical stain for cytokeratin 19 in a patient with longstanding liver
GVHD, illustrating ductular reaction at the periphery of a portal but without an identifiable
interlobular bile duct.
E.
A portal space showing absence of recognizable bile duct epithelium in a patient with
longstanding refractory chronic GVHD (H&E).
F.
Diffuse lobular inflammation, from a patient with a hepatitic onset of GVHD following
discontinuation of immunosuppressive drug therapy (H&E).
(Photomicrographs by Howard M. Shulman, M.D.)
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SUPPORTING FIGURE 3. Infections in the liver following hematopoietic cell transplant.
A. Fungal liver abscesses demonstrating the variability of findings in different samples. On the
left, a sterile healing abscess with a necrotic center devoid of fungal elements, surrounded by
inflammatory cells and a pseudo-capsule (asterisk) (H&E). On the right, an acute abscess with a
small focus of red-staining fungal elements (arrow) in a field of degenerative neutrophils,
surrounded by a pseudo-capsule (PAS).
B. Immunohistochemistry for hepatitis B core antigen, in a patient with fulminant hepatitis B
after transplant, showing extensive periportal hepatocyte cytoplasmic and some nuclear staining.
C.
Focal microabscess (arrow) in the liver lobule caused by cytomegalovirus, in which
lymphocytes and neutrophils are seen adjacent to enlarged, brick-red cells containing CMV
(H&E)
D. Confluent hepatocyte necrosis caused by Adenovirus infection; in the rim of hepatocytes
surrounding the necrotic area are darker “smudged nuclei” typical of Adenovirus (H&E).
E. Confluent hepatcyte necrosis (upper right) caused by Varicella Zoster Virus infection, with
absence of PAS staining of necrotic cells.
F. Diffuse infiltration by plasmacytoid cells and immunoblasts with displacement of portal
structures, caused by Epstein-Barr Virus lymphoproliferative disease (H&E).
(Photomicrographs by Howard M. Shulman, M.D.)
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SUPPORTING APPENDIX 1. OVERVIEW OF HEMATOPOIETIC CELL TRANSPLANTATION.
For in-depth reading on this subject, I recommend this textbook: Appelbaum FR, Forman SJ,
Negrin RS, Blume KG. Thomas' Hematopoietic Cell Transplantation. 4th ed. Oxford, UK:
Wiley-Blackwell Publishing, 2009.
There are three sources of hematopoietic cells used in HCT:
1) A person’s own cells, harvested by either bone marrow aspiration or by apheresis of
growth factor-mobilized peripheral blood (autologous transplant). There are only two
indications for autologous transplant: malignant disorders requiring high-intensity
chemotherapy (with or without radiation therapy) that would otherwise destroy marrow
function, and some autoimmune diseases under experimental protocols (for Crohn’s
disease, systemic sclerosis, and multiple sclerosis, for example).
If a malignancy
involves the marrow, an autologous transplant containing easily detected numbers of
malignant cells is contraindicated. If a patient has an autoimmune disease, the hypothesis
being tested is that high-dose, myeloablative chemotherapy followed by infusion of
autologous hematopoietic cells will reset the “immunostat” and result in less
inflammation.
2) Some one else’s cells, again harvested from either marrow or peripheral blood
(allogeneic transplant or, if an identical twin is available, syngeneic transplant). The
ideal allogeneic donor is an HLA-matched sibling, but patients without matched siblings
can have transplants from family members who are not siblings or from unrelated donors
who are HLA-matched with the patient. These unrelated donors are identified from
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
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international registries of people who have volunteered to be HLA-typed and who are
willing to have their hematopoietic cells harvested. There are many different indications
for allogeneic or syngeneic transplant: malignant disorders such as leukemia, lymphoma,
and myeloma; genetic disorders involving hematopoietic cells, immune cells, or cells
derived from these lineages; and some acquired hematologic disorders such as aplastic
anemia. Allogeneic cells can be infused after a myeloablative conditioning regimen,
resulting in complete hematopoietic cell chimerism (see the glossary in Supporting
Appendix 2), or after a reduced-intensity regimen, resulting in mixed host-donor
hematopoietic cell chimerism. The original intent of allogeneic transplantation was to
rescue patients whose marrow had been obliterated by high-dose anti-cancer therapy in
the conditioning regimen, where the anti-cancer therapy was thought to be the primary
modality that obliterated tumor cells. It is now apparent that allogeneic donor cells can
have significant effects on tumor cells, resulting in graft-vs.-tumor or graft-vs.-leukemia
effects.
All recipients of allogeneic hematopoietic cells must receive prophylactic
immune suppressive drugs to prevent acute graft-vs.-host disease.
3) Hematopoietic cells from the umbilical cord of a newborn infant (cord blood transplant).
Although hematopoietic cells obtained from cord blood are by definition allogeneic to
any patient into whom they are infused (other than the same newborn, but later in life),
these cells are immunologically immature, and are somewhat less prone to cause acute
graft-vs.-host disease. Most cord blood cells are HLA-mismatched with the patient into
whom they are infused. All recipients of allogeneic cord blood cells must receive
prophylactic immune suppressive drugs to prevent acute graft-vs.-host disease.
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Two types of conditioning therapy are used to prepare patients for the infusion of hematopoietic
cells. Without this conditioning therapy, a donor’s allogeneic cells would be rejected by the
recipient’s immune cells. In patients with a malignant disorder, the conditioning regimen usually
contains chemotherapy agents or radiation doses that have anti-tumor effects in addition to their
immune suppressive effects.
1) Myeloablative conditioning therapy may consist of many different combinations and
doses of chemotherapy drugs, with or without irradiation. Irradiation can be given as
Total Body Irradiation (from 10 to 16 Gy) or as radiolabeled antibodies designed to target
antigens on tumor cells. As noted in the body of this review, while all myeloablative
regimens are effective in obliterating virtually all hematopoietic and immune cells, not all
myeloablative conditioning regimens have equivalent organ toxicity, including liver
toxicity.
2) Reduced-intensity conditioning therapy consists of lower doses of chemotherapy and
immune-suppressive drugs, usually combined with lower dose Total Body Irradiation (for
example, 2-4 Gy). The intent is to prevent rejection of donor allogeneic cells so that
mixed chimerism can be established. In patients with malignant disorders, particularly
leukemia and lymphoma, donor allogeneic cells can eliminate hematopoietic cells,
immune cells and malignant cells of recipient origin, thus, achieving complete
hematopoietic cell chimerism and clearing of malignant cells. While this is the desired
effect of reduced-intensity allografting for malignant disorders, this result is not always
achieved. Current research examines the biology of graft-vs.-tumor effects and methods
to achieve more predictable anti-tumor effects after allogeneic transplant. In patients
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with certain non-malignant hematologic disorders and in-born errors of metabolism,
mixed hematopoietic chimerism is sufficient to correct phenotypic defects and “cure” the
underlying disorders.
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SUPPORTING APPENDIX 2. GLOSSARY OF COMMONLY USED TERMS AND JARGON WORDS IN THE
FIELD OF HEMATOPOIETIC CELL TRANSPLANTATION.
TERM OR JARGON WORD
MEANING
REFERRING TO THE PREPARATION OF PATIENTS FOR TRANSPLANTATION
Conditioning (as “conditioning
Treatment with drugs and/or irradiation to achieve anti-
therapy”, “the conditioning
tumor and immune suppressive effects. Conditioning
regimen”, “cytoreductive therapy”,
regimens can be myeloablative (lethal doses that ablate
or “the preparative regimen”)
marrow cells) or of reduced-intensity (lower doses where
the goal is immune suppression that avoids some of the
toxicity of myeloablative regimens, allowing mixed hostdonor chimerism to be achieved after transplant).
TBI, total body irradiation
Irradiation usually given by linear accelerator, with total
doses from 10 - 14 Gy (~1000 – 1400 rad) for
myeloablative regimens, and from 2-4 Gy (200 – 400 rad)
for reduced intensity regimens. The dose rate and the
schedules of delivery (single dose, fractionated,
hyperfractioned) vary widely around the world.
TLI, total lymphoid irradiation
Therapeutic irradiation selectively delivered to the spleen
and anatomic sites that harbor lymph nodes, including the
neck, mediastinum, supraclavicular regions and axillae
(“mantle”), periaortic, iliac, and femoral (“inverted Y”)
regions.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
TMI, total marrow irradiation
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Therapeutic irradiation selectively delivered to marrow
sites, including the spine, pelvis, and proximal long
bones, sometimes delivered as radioisotopes through the
use of bone-seeking agents.
Abbreviations for individual
BU, busulfan; TBU, targeted busulfan; CY,
cytoreductive drugs used in
cyclophosphamide; FLU, fludarabine; MEL, melphalan;
conditioning regimens
TT, thioTEPA; VP-16, etoposide
ATG, antithymocyte globulin, aka
Potent anti-T cell antibody made by immunizing rabbits
thymoglobulin
or horses with human cells; can be used as an
immunosuppressive agent in the conditioning regimen or
for treatment of acute graft-vs.-host disease
Peripheral blood stem cell
Techniques for collecting hematopoietic cells from the
mobilization and collection
circulation following administration of granulocytecolony stimulating factor (with or without prior
chemotherapy). Apheresis is used to collect blood
leukocytes enriched for hematopoietic stem cells that
normally reside in the marrow.
Disease abbreviations
AA, aplastic anemia; ALL, acute lymphocytic leukemia;
AML, acute myeloid leukemia; BRCA, breast cancer;
CLL, chronic lymphocytic leukemia; CML, chronic
myeloid leukemia (often subclassified as CP, chronic
phase, or AP, accelerated phase, or BC, blast crisis); HD,
Hodgkin’s disease; MDS, myelodysplastic syndrome;
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MM, multiple myeloma; NHL, non-Hodgkin’s
lymphoma; RA, refractory anemia; RAEB, refractory
anemia with excess blasts; RCMD, refractory cytopenia
with myelodysplasia
REFERRING TO THE SOURCE OF CELLS FOR THE TRANSPLANT
Hematopoietic cell transplantation
A term that encompasses all souces of cells that restore
(HCT, sometimes HSCT)
hematological and immunological function. Some centers
use the term “hematopoieic stem cell transplantation”.
Bone marrow transplantation
Transplantion that involves aspiration of bone marrow
(BMT)
cells, sieving to remove bony particles, then reinfusion
into a recipient
Peripheral blood stem cell (PBSC)
Transplantation using a source of hematopoietic precursor
transplantation
cells derived from the peripheral circulation
Cord blood transplantation
Transplantation using a source of hematopoietic precursor
cells derived from the umbilical vein of newborn infants;
these infants may or may not be related to their intended
recipient
T cell depletion
In allogeneic transplantation, a process whereby T
lymphocyte subsets are removed from the infusate of
donor hematopoietic cells; the intent is to decrease the
likelihood of the recipient developing acute graft-vs.-host
disease
Allogeneic transplantation
From one person to another
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
HLA, human leukocyte antigen
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A set of highly polymorphic antigens encoded by genes in
the major histocompatibility complex located on the short
arm of chromosome 6
HLA-matched, or -mismatched
In allogeneic transplantion, the designation of the
relationship of the donor’s HLA type to that of the
recipient. HLA-matched means that the donor and
recipient have identical types for the antigens tested.
HLA-mismatched means that the antigens of donor and
recipient are discrepant.
Unrelated donor
A donor who is HLA-matched to the candidate for
transplant, usually someone who has volunteered to be
HLA typed as part of an international registry of potential
donors.
Autologous transplantation
Reinfusion of one’s own hematopoietic cells (from
peripheral blood or marrow)
Syngeneic or isogeneic
From one identical twin to another
transplantation
Day zero
By convention, the day on which infusion of
hematopoietic cells is completed; all subsequent events
are numbered with reference to this day, as in “day 1”,
meaning the first day after the infusion.
OTHER TERMS AND ABBREVIATIONS COMMONLY USED IN THE PERI-TRANSPLANT PERIOD
Hematopoietic growth factors
G-CSF, granulocyte colony stimulating factor; GM-CSF,
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granulocyte-macrophage colony stimulating factor; SCF,
stem cell factor
Antimicrobial drugs
TMP-SMX, trimethoprim-sulfamethoxazole; AMB,
amphotericin B; DHPG or GCV, ganciclovir; ACV,
acyclovir; 3-TC, lamivudine
Immunosuppressive drugs
CSP or CSA, cyclosporine; FK506 or “tac”, tacrolimus;
MTX, methotrexate; MMF, mycophenolate mofetil;
ATG, antithymocyte globulin
Viruses
HSV, herpes simplex virus; CMV, cytomegalovirus;
RSV, respiratory syncytial virus; HHV-6, human herpes
virus 6; VZV, varicella zoster virus; EBV, Epstein-Barr
virus
Seropositive or CMV seropositive
Presence of antibodies to CMV in blood samples from the
patient before transplant, or from the donor, indicating
prior CMV infection. The risk of CMV infection in the
recipient after transplant is low when both patient and
donor are seronegative. CMV can be activated from
latency and can replicate when either the recipient or the
donor has been previously infected.
CMV antigen or DNA positive
A blood test that detects either a CMV protein antigen or
DNA in circulating leukocytes in the recipient, after
transplant. A positive result indicates CMV infection, in
contrast to CMV disease, where there is organ
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dysfunction caused by CMV.
REFERRING TO THE
STATE OF HEMATOPOIETIC CELL ENGRAFTMENT POST TRANSPLANT
Hematological acronyms
ANC, absolute neutrophil count; PLTS, platelets; Hct,
hematocrit
Failure to engraft
No signs of donor hematopoietic cells are seen in either
peripheral blood or marrow post transplant
Engraftment
Appearance of donor hematopoietic cells in the peripheral
blood or marrow post transplant, usually with concordant
appearance of donor-derived leukocyte, red blood cell,
and platelet lineages. By convention, engraftment is
defined as ANC > 500/mm3, platelets > 20,000/mm3, or
platelets >50,000/mm3.
Graft rejection
Disappearance of donor hematopoietic cells after signs of
engraftment
Mixed chimerism
A result of allogeneic transplantation in which both donor
and host hematopoietic cells co-exist in the recipient
Complete chimerism
A result of allogeneic transplantation in which all
hematopoietic and lymphoid cells are of donor origin
Platelet transfusion dependent
A state where platelet transfusions are needed to maintain
a patient’s platelet counts above an arbitrary level, usually
10,000/mm3
REFERRING TO GRAFT - VERSUS - HOST DISEASE
GVHD
An immunological process whereby donor-derived T
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lymphocytes cause damage in recipient tissues; there are
two forms of GVHD, acute and chronic
Acute GVHD
Immune-mediated damage to skin, gastrointestinal
mucosa, and liver that occurs from the time of transplant
to day 200. Occurs in 40 – 60% of allografts, in 10-15%
of autograftsa, and rarely after syngeneic transplantb.
Chronic GVHD
A pleomorphic syndrome that affects the lacrimal glands,
salivary glands, squamous mucosa (skin, mouth,
esophagus, and vagina), lungs, muscle and tendons, and
immune system. Often overlaps with protracted acute
GVHD involving the gut and liver.
Hyperacute GVHD
Acute GVHD that occurs earlier than expected, usually
before day 10, often with capillary leak syndrome and
rapidly progressive skin rash, high-volume diarrhea, and
jaundice.
GVHD prophylaxis
Immune suppressive drugs given during the peritransplant period and extended to day 70-80 to prevent or
ameliorate the intensity of acute GVHD. Commonly used
drugs include methotrexate, cyclosporine, tacrolimus,
mycophenolate mofetil, high-dose cyclophosphamide, in
different combinations.
Stage and grade of GHVD
Categoric variables for assessing the extent of damage to
skin, gut, and liver (stage) and the overall severity of
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acute GVHD (I-IV in the Americas, A-D in Europe).
Not evidence-based but generally descriptive of severity.
Acute GVHD Activity Index
An evidence-based tool for predicting non-relapse
mortality in patients with acute GVHD, based on four
variables (total serum bilirubin, anorexia, need for
immune suppression, and performance).
Primary treatment of GVHD
Immunosuppressive medication given to patients in
whom a diagnosis of acute GVHD is first made; to be
distinguished from prophylactic treatment and secondary
treatment of GVHD; usually involves addition of
prednisone at a dose of 1 - 2 mg/kg/day to the prophylaxis
regimen
Secondary treatment of GVHD
Medication that is given to patients whose acute GVHD
has not responded to primary treatment regimens; usually
involves additional immunosuppressive drugs such as
MMF, anti-T cell antibodies, anti-cytokine biological
therapies, or prednisone pulses of >2 mg/kg/day, in
various combinations.
REFERRING TO THE OUTCOME OF HEMATOPIETIC CELL TRANSPLANTATION
Relapse
Reappearance of the malignancy for which the transplant
was carried out.
Cytogenetic relapse
Abnormal cytogenetics or genetic test without detectable
abnormal cell morphology
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
Donor lymphocyte infusion (DLI)
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Donor cells, given after relapse of malignancy in order to
produce a graft-vs.-tumor effect
Non-relapse mortality
Death in a patient whose underlying malignancy had not
relapsed.
Second transplant
Refers to a second conditioning regimen, followed by a
second infusion of hematopoietic cells, usually for
persistence or recurrence of malignancy. In allogeneic
second transplants, a different donor is often chosen in an
attempt to produce better graft-vs.-tumor effect.
Tandem transplant
A planned treatment, usually for myeloma, where an
autologous transplant with myeloablative conditioning is
followed by allogeneic transplant with reduced-intensity
conditioning.
a
Holmberg L, Kikuchi K, Gooley T, Adams KM, Hockenbery DM, Flowers MED, Schoch HG,
et al. Gastrointestinal graft-versus-host disease in recipients of autologous hematopoietic stem
cells: Incidence, risk factors, and outcome. Biology of Blood and Marrow Transplantation
2006; 12: 226 – 234.
b
Adams KM, Holmberg LA, Leisenring W, Guthrie KA, Tylee TS, McDonald GB, Bensinger
WI, et al. Risk factors for syngeneic graft-versus-host disease after adult hematopoietic stem cell
transplantation. Blood 2004; 104: 1894 – 1897.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
SUPPORTING APPENDIX 3.
ABBREVIATIONS
COMMONLY
USED
HEMATOPOIETIC CELL TRANSPLANTATION.
ABBREVIATION
MEANING
AA
Aplastic Anemia
aGVHD
Acute Graft-vs.-host disease
ALL
Acute Lymphocytic Leukemia
AML
Acute Myelogenous Leukemia
ANC
Absolute Neutrophil Count
ANL
Acute Non-lymphocytic Leukemia
ATG
AntiThymocyte Globulin
BMT
Bone Marrow Transplant
BU
BUsulfan
BU/CY or CY/BU
BUsulfan and CYclophosphamide
cGVHD
chronic GVHD
cGy
centigray (0.01 Gy), or ~ 1 rad
CLL
Chronic Lymphocytic Leukemia
CML
Chronic Myeloid Leukemia
CMV
cytomegalovirus
CSP or CSA
cyclosporine
CY
CYclophosphamide
CY/TBI or TBI/CY
CYclophosphamide and Total Body Irradiation
DLI
Donor Lymphocyte Infusion
IN
THE
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FIELD
OF
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EBV
Epstein-Barr Virus
FLU
Fludarabine
G-CSF
Granulocyte colony stimulating factor
GM-CSF
Granulocyte-macrophage colony stimulating factor
GVHD
Graft-Versus-Host Disease (see aGVHD and Cgvhd)
GVHDAI
Graft-Versus-Host Disease Activity Index
GVL
Graft Versus Leukemia
Gy
Grey, a radiation dose
HCT
Hematopoietic Cell Transplant
HD
Hodgkin’s Disease
HHV-6 or -8
Human Herpes Virus-6 or -8
HLA
Human Leukocyte-Associated (antigens)
HLA-MM
HLA-mismatched
HSCT
hematopoietic stem cell transplant
HSV
Herpes Simplex Virus
MDS
Myelodysplastic Syndrome
MEL
melphalan
MM
Multiple Myeloma
MMF
Mycophenolate Mofetil
MTX
Methotrexate
MURD
(HLA) Matched UnRelated Donor
NHL
Non-Hodgkin’s Lymphoma
NRM
Non-Relapse Mortality, death in the absence of a relapse of malignancy
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
PLTS
Platelet count
PBSCT
Peripheral Blood Stem Cell Transplant
RA
Refractory Anemia
RAEB
Refractory Anemia with Excess Blasts
RRT
Regimen-Related Toxicity
SCF
Stem Cell Factor
SOS
Sinusoidal Obstruction Syndrome (aka VOD)
TBI
Total Body Irradiation
TT
ThioTEPA
TLI
Total Lymphoid Irradiation
TMI
Total Marrow Irradiation
TMP-SMX
Trimethoprim-sulfamethoxazole
URD
Unrelated donor of hematopoietic cells
VOD
Veno-Occlusive Disease, now known as Sinusoidal Obstruction
Syndrome
VP-16
Etoposide
VZV
Varicella Zoster Virus
WHVPG
Wedged Hepatic Venous Pressure Gradient
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SUPPORTING APPENDIX 4. SUPPLEMENTARY TOPIC-ORIENTED READING LIST.
EVALUATION OF LIVER PROBLEMS BEFORE TRANSPLANT
FUNGAL LIVER INFECTIONS
Anttila VJ, Lamminen AE, Bondestam S, Korhola O, Farkkila M, Sivonen A, Ruutu T, et al.
Magnetic resonance imaging is superior to computed tomography and ultrasonography in
imaging infectious liver foci in acute leukaemia. Eur J Haematol 1996;56:82-87.
Ostrosky-Zeichner L, Alexander BD, Kett DH, Vazquez J, Pappas PG, Saeki F, Ketchum PA, et
al. Multicenter clinical evaluation of the (1-->3) beta-D-glucan assay as an aid to diagnosis of
fungal infections in humans. Clinical Infectious Diseases 2005;41:654-659.
Mennink-Kersten MASH, Donnelly JP, Verweij PE. Detection of circulating galactomannan for
the diagnosis and management of invasive aspergillosis. The Lancet Infectious Diseases
2004;4:349-357.
Rossetti F, Brawner DL, Bowden RA, Meyer WG, Schoch HG, Fisher L, Myerson D, et al.
Fungal liver infection in marrow transplant patients: prevalence at autopsy, predisposing factors,
and clinical features. Clinical Infectious Diseases 1995;20:801-811.
van Burik JH, Leisenring W, Myerson D, Hackman RC, Shulman HM, Sale GE, Bowden RA, et
al. The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
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marrow transplant recipients with special attention to hepatic candidiasis: An autopsy study of
355 patients. Medicine (Baltimore) 1998;77:246-254.
VIRAL HEPATITIS
Hui C-k, Lie A, Au W-y, Ma S-y, Leung Y-H, Zhang H-y, Sun J, et al. Effectiveness of
prophylactic anti-HBV therapy in allogeneic hematopoietic stem cell transplantation with
HBsAg positive donors. American Journal of Transplantation 2005;5:1437-1445.
Piekarska A, Zaucha JM, Hellman A, McDonald GB. Prevention of hepatitis B virus (HBV)
transmission from an infected stem cell donor. Bone Marrow Transplantation 2007;40:399-400.
Vance EA, Soiffer RJ, McDonald GB, Myerson D, Fingeroth J, Ritz J. Prevention of
transmission of hepatitis C virus in bone marrow transplantation by treating the donor with
alpha-interferon. Transplantation 1996;62:1358-1360.
Ramos CA, Saliba RM, de Padua L, Khorshid O, Shpall EJ, Giralt S, Patah PA, et al. Impact of
hepatitis C virus seropositivity on survival after allogeneic hematopoietic stem cell
transplantation for hematologic malignancies. Haematologica 2009;94:249-257.
LIVER DISEASES AT BASELINE
Shulman HM, McDonald GB: Hepatic complications of hematopoietic cell transplantation. In:
Gershwin ME, Vierling JM, Manns M, eds. Liver Immunology: Principles and Practice. Totowa,
NJ: Humana Press, 2007; 409-421.
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Ohyashiki K, Kuriyama Y, Nakajima A, Tauchi T, Ito Y, Miyazawa H, Kimura Y, et al. Imatinib
mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis
resembling acute viral hepatitis. Leukemia 2002;16:2160-2161.
Ayoub WS, Geller SA, Tran T, Martin P, Vierling JM, Poordad FF. Imatinib (Gleevec)-induced
hepatotoxicity. Journal of Clinical Gastroenterology 2005;39:75-77.
Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, et al. Prior
gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in
patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003;102:15781582.
GALLSTONES
Safford SD, Safford KM, Martin P, Rice H, Kurtzberg J, Skinner MA. Management of
cholelithiasis in pediatric patients who undergo bone marrow transplantation. Journal of Pediatric
Surgery 2001;36:86-90.
IRON OVERLOAD
St Pierre TG, Clark PR, Chua-anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK, Pootrakul P, et
al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic
resonance. Blood 2005;105:855-861.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 24
Kontoyiannis DP, Chamilos G, Lewis RE, Giralt S, Cortes J, Raad II, Manning JT, et al.
Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in
patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic
stem cell transplantation. Cancer 2007;110:1303-1306.
Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, Andreani M, et al.
Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. New
England Journal of Medicine 1993;329:840-844.
Foerder CA, Tobin AA, McDonald GB, Zager RA. Bleomycin-detectable iron in plasma of
bone-marrow transplant patients: its correlation with liver injury. Transplantation 1992;54:11201123.
Tomas JF, Pinilla I, Garcia-Buey ML, Garcia A, Gomez-Garcia de Soria V, R. M, FernandezRanada JM. Long-term liver dysfunction after allogeneic bone marrow transplantation: Clinical
features and course in 61 patients. Bone Marrow Transplantation 2000;26:649-655.
HEPATOBILIARY PROBLEMS FROM TRANSPLANT THROUGH DAY 200
SINUSOIDAL OBSTRUCTION SYNDROME
McDonald GB, Hinds MS, Fisher LB, Schoch HG, Wolford JL, Banaji M, Hardin BJ, et al.
Venocclusive disease of the liver and multiorgan failure after bone marrow transplantation: A
cohort study of 355 patients. Annals of Internal Medicine 1993;118:255-267.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 25
DeLeve LD, Valla DC, Garcia-Tsao G, American Association for the Study Liver Disease.
Vascular disorders of the liver. Hepatology 2009;49:1729-1764.
McDonald GB, McCune JS, Batchelder A, Cole S, Phillips B, Ren AG, Vicini P, et al.
Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant. Clinical
Pharmacology & Therapeutics 2005;78:298-308.
Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, McDonald GB.
Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004;103:1557-1559.
Hagglund H, Remberger M, Klaesson S, Lonnqvist B, Ljungman P, Ringden O. Norethisterone
treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone
marrow transplantation. Blood 1998;92:4568-4572.
Cutler C, Stevenson K, Haesook TK, Richardson PG, Vincent TH, Linden E, Revta C, et al.
Sirolimus is associated with veno-occlusive disease of the liver after myeloblative allogeneic
stem cell transplantation. Blood 2008;112:4425-4431.
Corbacioglu S, Honig M, Lahr G, Stohr S, Berry G, Friedrich W, Schulz AS. Stem cell
transplantation in children with infantile osteopetrosis is associated with a high incidence of
VOD, which could be prevented with defibrotide. Bone Marrow Transplantation 2006;38:547553.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 26
Cheuk DK, Wang P, Lee TL, Chiang AK, Ha SY, Lau YL, Chan GC. Risk factors and mortality
predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell
transplantation. Bone Marrow Transplantation 2007;40:935-944.
Tay J, Tinmouth A, Fergusson D, Huebsch L, Allan DS. Systematic review of controlled clinical
trials on the use of ursodeoxycholic acid for the prevention of hepatic veno-occlusive disease in
hematopoietic stem cell transplantation. Biology of Blood & Marrow Transplantation
2007;13:206-217.
Hasegawa S, Horibe K, Kawabe T, Kato K, Kojima S, Matsuyama T, Hirabayashi N. Venoocclusive disease of the liver after allogeneic bone marrow transplantation in children with
hematologic malignancies: incidence, onset time and risk factors. Bone Marrow Transplantation
1998;22:1191-1197.
Lee JL, Gooley T, Bensinger W, Schiffman K, McDonald GB. Venocclusive disease of the liver
after busulfan, melphalan, and thioTEPA conditioning therapy: Incidence, risk factors, and
outcome. Biology of Blood & Marrow Transplantation 1999;5:306-315.
Toh HC, McAfee SL, Sackstein R, Cox BF, Colby C, Spitzer TR. Late onset veno-occlusive
disease following high-dose chemotherapy and stem cell transplantation. Bone Marrow
Transplantation 1999;24:891-895.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 27
Rajvanshi P, Shulman HM, Sievers EL, McDonald GB. Hepatic sinusoidal obstruction following
Gemtuzumab ozogamicin (Mylotarg) therapy. Blood 2002;99:4245-4246.
Pihusch M, Wegner H, Goehring P, Salat C, Pihusch V, Hiller E, Andreesen R, et al. Diagnosis
of hepatic veno-occlusive disease by plasminogen activator inhibitor-1 plasma antigen levels: a
prospective analysis in 350 allogeneic hematopoietic stem cell recipients. Transplantation
2005;80:1376-1382.
Lassau N, Auperin A, Leclere J, Bennaceur A, Valteau-Couanet D, Hartmann O. Prognostic
value of doppler-ultrasonography in hepatic veno-occlusive disease. Transplantation.
2002;74:60-66.
Erturk SM, Mortele KJ, Binkert CA, Glickman JN, Oliva M-R, Ros PR, Silverman SG. CT
features of hepatic venoocclusive disease and hepatic graft-versus-host disease in patients after
hematopoietic stem cell transplantation. American Journal of Roentgenology 2006;186:14971501.
Hashiguchi M, Okamura T, Yoshimoto K, Ono N, Imamura R, Yakushiji K, Ogata H, et al.
Demonstration of reversed flow in segmental branches of the portal vein with hand-held color
Doppler ultrasonography after hematopoietic stem cell transplantation. Bone Marrow
Transplantation 2005;36:1071-1075.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 28
McCarville MB, Hoffer FA, Howard SC, Goloubeva O, Kauffman WM. Hepatic veno-occlusive
disease in children undergoing bone-marrow transplantation:
usefulness of sonographic
findings. Pediatric Radiology 2001;31:102-105.
Choi SW, Islam S, Greenson JK, Levine J, Hutchinson R, Yanik G, Teitelbaum DH, et al. The
use of laparoscopic liver biopsies in pediatric patients with hepatic dysfunction following
allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation 2005;36:891896.
Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth
doing should be done right. Hepatology. 2004;39:280-282.
Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically ventilated recipients
of bone marrow transplants: a case for evidence-based guidelines. Ann Intern Med
1996;125:625-633.
Salinger DH, McCune JS, Ren AG, Shen DD, Slattery JT, Phillips B, McDonald GB, et al. Realtime dose adjustment of cyclophosphamide in a preparative regimen for hematopoietic cell
transplant: a Bayesian pharmacokinetic approach. Clinical Cancer Research 2006;12:4888-4898.
Slattery JT, Clift RA, Buckner CD, Radich J, Storer B, Bensinger WI, Soll E, et al. Marrow
transplantation for chronic myeloid leukemia - the influence of plasma busulfan levels on the
outcome of transplantation. Blood 1997;89:3055-3060.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 29
Shaw PJ, Scharping CE, Brian RJ, Earl JW. Busulfan pharmacokinetics using a single daily
high-dose regimen in children with acute leukemia. Blood 1994;84:2357-2362.
Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L, Parkkali T, et al. A
randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic
marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow
Transplantation Group. Blood 1994;83:2723-2730.
Shulman HM, Gown AM, Nugent DJ. Hepatic veno-occlusive disease after bone marrow
transplantation. Immunohistochemical identification of the material within occluded central
venules. Am J Pathol 1987;127:549-558.
Kikuchi K, Rudolph R, Murakami C, Kowdley KV, McDonald GB. Portal vein thrombosis after
hematopoietic cell transplantation: frequency, treatment, and outcome. Bone Marrow
Transplantation 2002;29:329-333.
Pihusch M, Wegner H, Goehring P, Salat C, Pihusch V, Andreesen R, Kolb HJ, et al. Protein C
and procollagen III peptide levels in patients with hepatic dysfunction after allogeneic
hematopoietic stem cell transplantation. Bone Marrow Transplantation 2005;36:631-637.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 30
Kallianpur AR, Hall LD, Yadav M, Byrne DW, Speroff T, Dittus RS, Haines JL, et al. The
hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after
hematopoietic stem cell transplantation. Bone Marrow Transplantation 2005;35:1155-1164.
Kallianpur AR. Genomic screening and complications of hematopoietic stem cell
transplantation: has the time come? Bone Marrow Transplantation 2005;35:1-16.
Srivastava A, Poonkuzhali B, Shaji RV, George B, Mathews V, Chandy M, Krishnamoorthy R.
Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in
bone marrow transplantation. Blood 2004;104:1574-1577.
Bornhauser M, Storer B, Slattery J, Appelbaum F, Deeg H, Hansen J, Martin P, et al.
Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic
hematopoietic stem cells. Blood 2003;102:820-826.
Anderson JE, Appelbaum FR, Schoch G, Barnett T, Chauncey TR, Flowers ME, Storb R.
Relapse after allogeneic bone marrow transplantation for refractory anemia is increased by
shielding lungs and liver during total body irradiation. Biology of Blood & Marrow
Transplantation 2001;7:163-170.
Meresse V, Hartmann O, Vassal G, Benhamou E, Vatteau-Couenet D, Brugieres L, Lemerle J.
Risk factors of hepatic venocclusive disease after high-dose busulfan-containing regimens
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 31
followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow
Transplant 1992;10:135-141.
Hassan M, Ljungman P, Ringden O, Hassan Z, Oberg G, Nilsson C, Bekassy A, et al. The effect
of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time
interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow
Transplantation. 2000;25:915-924.
Wang X, Kanel GC, DeLeve LD. Support of sinusoidal endothelial cell glutathione prevents
hepatic veno-occlusive disease in the rat. Hepatology 2000;31:428-434.
Geraci JP, Mariano MS, Jackson KL. Radiation hepatopathy of the rat: microvascular fibrosis
and enhancement of liver dysfunction by diet and drugs. Radiat Res 1992;129:322-332.
Lee J-H, Choi S-J, Lee J-H, Kim S-E, Park C-J, Chi H-S, Lee M-S, et al. Decreased incidence of
hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous
busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic
bone marrow transplantation. Annals of Hematology 2005;84:321-330.
Radich JP, Gooley T, Bensinger W, Chauncey T, Clift R, Flowers M, Martin P, et al. HLAmatched related hematopoietic cell transplantation for chronic-phase CML using a targeted
busulfan and cyclophosphamide preparative regimen. Blood 2003;102:31-35.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 32
Deeg HJ, Storer BE, Boeckh M, Martin PJ, McCune JS, Myerson D, Heimfeld S, et al. Reduced
incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a
targeted busulfan/cyclophosphamide regimen. Biology of Blood & Marrow Transplantation
2006;12:573-584.
Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W, Blume K, et al. Intravenous
versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic
hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease
(HVOD), HVOD-related mortality, and overall 100-day mortality. Biology of Blood & Marrow
Transplantation 2002;8:493-500.
Williams CB, Day SD, Reed MD, Copelan EA, Bechtel T, Leather HL, Wingard JR, et al. Dose
modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by
autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic
malignancies. Biology of Blood & Marrow Transplantation 2004;10:614-623.
Deleve LD, Wang X, Tsai J, Kanel G, Strasberg S, Tokes ZA. Sinusoidal obstruction syndrome
(veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition.
Gastroenterology. 2003;125:882-890.
Chalandon Y, Roosnek E, Mermillod B, Newton A, Ozsahin H, Wacker P, Helg C, et al.
Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation.
Biology of Blood & Marrow Transplantation 2004;10:347-354.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 33
Versluys B, Bhattacharaya R, Steward C, Cornish J, Oakhill A, Goulden N. Prophylaxis with
defibrotide prevents veno-occlusive disease in stem cell transplantation after gemtuzumab
ozogamicin exposure. Blood. 2004;103:1968.
Imran H, Tleyjeh IM, Zirakzadeh A, Rodriguez V, Khan SP. Use of prophylactic anticoagulation
and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell
transplantation: a systematic review and meta-analysis. Bone Marrow Transplantation
2006;37:677-686.
Bearman SI, Hinds MS, Wolford JL, Petersen FB, Nugent DL, Slichter SJ, Shulman HM, et al. A
pilot study of continuous infusion heparin for the prevention of hepatic venocclusive disease
after bone marrow transplantation. Bone Marrow Transplant 1990;5:407-411.
Budinger MD, Bouvier M, Shah A, McDonald GB. Results of a phase I trial of antithrombin III
as prophylaxis in bone marrow transplant patients at risk for venocclusive disease. Blood
1996;88:172a.
Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, Straham B, et al. Defibrotide
in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre
study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplantation
2004;33:189-195.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 34
Kornblum N, Ayyanar K, Benimetskaya L, Richardson P, Iacobelli M, Stein CA. Defibrotide, a
polydisperse mixture of single-stranded phosphodiester oligonucleotides with lifesaving activity
in severe hepatic veno-occlusive disease: clinical outcomes and potential mechanisms of action.
Oligonucleotides 2006;16:105-114.
Benimetskaya L, Wu S, Voskresenskiy AM, Echart C, Zhou JF, Shin J, Iacobelli M, et al.
Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic
veno-occlusive disease. Blood 2008;112:4343-4352.
Lazarus HM, McCrae KR. SOS! Defibrotide to the rescue. Blood 2008;112:3924-3925.
Azoulay D, Castaing D, Lemoine A, Hargreaves GM, Bismuth H. Transjugular intrahepatic
portosystemic shunts (TIPS) for severe veno-occlusive disease of the liver following bone
marrow transplantation. Bone Marrow Transplantation 2000;25:987-992.
Meacher R, Venkatesh B, Lipman J. Acute respiratory distress syndrome precipitated by
transjugular intrahepatic porto-systemic shunting for severe hepatic veno-occlusive disease. Is it
due to pulmonary leucostasis? Intensive Care Medicine 1999;25:1332-1333.
Koenecke C, Kleine M, Schrem H, Krug U, Nashan B, Neipp M, Ganser A, et al. Sinusoidal
obstruction syndrome of the liver after hematopoietic stem cell transplantation: decision making
for orthotopic liver transplantation. International Journal of Hematology 2006;83:271-274.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 35
Mellgren K, Fasth A, Saalman R, Olausson M, Abrahamsson J. Liver transplantation after stem
cell transplantation with the same living donor in a monozygotic twin with acute myeloid
leukemia. Annals of Hematology 2005;84:755-757.
Kim ID, Egawa H, Marui Y, Kaihara S, Haga H, Lin YW, Kudoh K, et al. A successful liver
transplantation for refractory hepatic veno-occlusive disease originating from cord blood
transplantation. American Journal of Transplantation 2002;2:796-800.
CHOLESTATIC LIVER DISORDERS
Malone FR, Leisenring W, Schoch G, Stern J, Aker S, Lawler R, McDonald GB. Prolonged
anorexia and elevated plasma cytokine levels following myeloablative allogeneic hematopoietic
cell transplant. Bone Marrow Transplant 2007;40:765-772.
Green RM, Beier D, Gollan JL. Regulation of hepatocyte bile salt transporters by endotoxin and
inflammatory cytokines in rodents. Gastroenterology 1996;111:193-198.
Chand N, Sanyal AJ. Sepsis-induced cholestasis. Hepatology 2007;45:230-241.
Bernuau D, Feldmann G, Degott C, Gisselbrecht C. Ultrastructural lesions of bile ducts in
primary biliary cirrhosis. A comparison with the lesions observed in graft versus host disease.
Human Pathology 1981;12:782-793.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 36
Quaranta S, Shulman HM, Paganin S, Schoenfeld Y, Peter J, Ahmed A, Leung PA, et al.
Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell
transplantation. Clinical Immunology 1999;91:106-116.
Saunders MD, Shulman HM, Murakami CS, Chauncey TR, Bensinger WI, McDonald GB. Bile
duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous
hematopoietic cell transplantation. American Journal of Surgical Pathology 2000;24:1004-1008.
Akpek G, Boitnott JK, Lee LA, Hallick JP, Torbenson M, Jacobsohn DA, Arai S, et al. Hepatitic
variant of graft-versus-host disease after donor lymphocyte infusion. Blood 2002;100:39033907.
Ma SY, Au WY, Ng IOL, Lie AKW, Leung AYH, Liang R, Lau GKK, et al. Hepatitic graftversus-host disease after hematopoietic stem cell transplantation: clinicopathologic features and
prognostic implication. Transplantation 2004;77:1252-1259.
Melin-Aldana H, Thormann K, Duerst R, Kletzel M, Jacobsohn DA. Hepatitic pattern of graft
versus host disease in children. Pediatric Blood & Cancer 2007;49:727-730.
Stockschlaeder M, Storb R, Pepe M, Longton G, McDonald GB, Anasetti C, Appelbaum FR, et
al. A pilot study of low dose cyclosporin for graft-versus-host prophylaxis in marrow
transplantation. Br J Haematol 1992;80:49-54.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 37
List AF, Spier C, Greer J, Wolff S, Hutter J, Dorr R, Salmon S, et al. Phase I/II trial of
cyclosporine as a chemotherapy-resistance modifier in acute leukemia J Clin Oncol
1993;11:1652-1660.
ACUTE HEPATOCELLULAR INJURY
Kim B, Chung K, Sun H, Suh J, Min W, Kang C, Sim S, et al. Liver disease during the first
posttransplant year in bone marrow transplantation recipients: retrospective study. Bone Marrow
Transplantation 2000;26:193-197.
Ho G-T, Parker A, MacKenzie JF, Morris AJ, Stanley AJ. Abnormal liver function tests
following bone marrow transplantation: aetiology and role of liver biopsy. European Journal of
Gastroenterology & Hepatology 2004;16:157-162.
Poon A, Ly L. Common potential drug interactions following hematopoietic cell transplantation.
In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG. Thomas' Hematopoietic Cell
Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell Publishing, 2009; 1523-1538.
Koc Y, Miller KB, Schenkein DP, Griffith J, Akhtar M, DesJardin J, Snydman DR. Varicella
zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors,
and clinical outcome. Biology of Blood & Marrow Transplantation 2000;6:44-49.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 38
Bordigoni P, Carret AS, Venard V, Witz F, Le Faou A. Treatment of adenovirus infections in
patients undergoing allogeneic hematopoietic stem cell transplantation. Clinical Infectious
Diseases 2001;32:1290-1297.
Baldwin A, Kingman H, Darville M, Foot AB, Grier D, Cornish JM, Goulden N, et al. Outcome
and clinical course of 100 patients with adenovirus infection following bone marrow
transplantation. Bone Marrow Transplantation 2000;26:1333-1338.
Bruno B, Gooley T, Hackman RC, Davis C, Corey L, Boeckh M. Adenovirus infection in
hematopoietic stem cell transplantation: effect of ganciclovir and impact on survival. Biology of
Blood & Marrow Transplantation 2003;9:341-352.
Walls T, Shankar AG, Shingadia D. Adenovirus: an increasingly important pathogen in
paediatric bone marrow transplant patients. The Lancet Infectious Diseases 2003;3:79-86.
Kuribayashi K, Matsunaga T, Iyama S, Takada K, Sato T, Murase K, Fujimi A, et al. Human
herpesvirus-6 hepatitis associated with cyclosporine-A encephalitis after bone marrow
transplantation for chronic myeloid leukemia. Internal Medicine 2006;45:475-478.
Muller WJ, Levin MJ, Shin YK, Robinson C, Quinones R, Malcolm J, Hild E, et al. Clinical and
in vitro evaluation of cidofovir for treatment of adenovirus infection in pediatric hematopoietic
stem cell transplant recipients. Clinical Infectious Diseases 2005;41:1812-1816.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 39
Lau GK, He M-L, Fong DYT, Bartholomeusz A, Au W, Lie AKW, Locarnini S, et al.
Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic
cell transplantation. Hepatology 2002;36:702-709.
Hui CK, Cheung WWW, Au WY, Lie AKW, Zhang HY, Yueng YH, Wong BCY, et al.
Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with
haematological malignancy on completion of cytotoxic chemotherapy. Gut 2005;54:1597-1603.
Lin P-C, Poh S-B, Lee M-Y, Hsiao L-T, Chen P-M, Chiou T-J. Fatal fulminant hepatitis B after
withdrawal of prophylactic lamivudine in hematopoietic stem cell transplantation patients.
International Journal of Hematology 2005;81:349-351.
de Latour RP, Asselah T, Levy V, Scieux C, Devergie A, Ribaud P, Esperou H, et al. Treatment
of chronic hepatitis C virus in allogeneic bone marrow transplant recipients. Bone Marrow
Transplantation 2005;36:709-713.
Honjo I, Suou T, Hirayama C. Hepatotoxicity of cyclophosphamide in man: Pharmacokinetic
analysis. Res Commun Chem Pathol Pharmacol 1988;61:149-165.
Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal
medications in bone marrow transplant recipients. Clinical Infectious Diseases 2005;41:301-307.
FUNGAL INFECTIONS
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 40
Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, et
al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. New
England Journal of Medicine 2007;356:335-347.
van Burik J-AH. Role of new antifungal agents in prophylaxis of mycoses in high risk patients.
Current Opinion in Infectious Diseases 2005;18:479-483.
GALLBLADDER AND BILIARY DISEASE
Ko CW, Murakami C, Sekijima JH, Kim MH, McDonald GB, Lee SP. Chemical composition of
gallbladder sludge in patients after marrow transplantation. Am J Gastroenterol 1996;91:12071210.
Ko CW, Gooley T, Schoch HG, Myerson D, Hackman RC, Shulman HM, Sale GE, et al. Acute
pancreatitis in marrow transplant patients: prevalence at autopsy and risk factor analysis. Bone
Marrow Transplant 1997;20:1081-1086.
Murakami CS, Louie W, Chan GS, O'Donnell M, David D, Forman SJ, McDonald GB. Biliary
obstruction in hematopoietic cell transplant recipients: an uncommon diagnosis with specific
causes. Bone Marrow Transplantation 1999;23:921-927.
MALIGNANT DISORDERS
Zutter MM, Martin PJ, Sale GE, Shulman HM, Fisher L, Thomas ED, Durnam DM. Epstein-barr
virus lymphoproliferation after bone marrow transplantation. Blood 1988;72:520-529.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 41
HEPATOBILIARY PROBLEMS IN LONG-TERM TRANSPLANT SURVIVORS
CHRONIC GVHD
Sakai M, McDonald GB: Gastrointestinal and hepatic manifestations of chronic GVHD. In:
Vogelsang GB, Pavletic SZ, eds. Chronic graft-versus-host disease: Interdisciplinary
management. First ed. New York, New York: Cambridge University Press, 2009; 216-226.
Jagasia M, Shulman HM, Filipovich AH, Pavletic S: Diagnosis and Staging. In: Vogelsang GB,
Pavletic SZ, eds. Chronic graft-versus-host disease: Interdisciplinary management. First ed. New
York, New York: Cambridge University Press, 2009; 87-100.
Malik AH, Collins JRH, Saboorian MH, Lee WM. Chronic graft versus host disease (GVHD)
following hematopoietic cell transplantation (HCT) presenting as an acute hepatitis. American
Journal of Gastroenterology 2001;96:588-590.
Mullighan CG, Bogdanos DP, Vergani D, Bardy PG. Cytochrome P450 1A2 is a target antigen
in hepatitic graft-versus-host disease. Bone Marrow Transplantation 2006;38:703-705.
Martin PJ, Gilman AL: Front Line Treatment of Chronic Graft Versus Host Disease. In:
Vogelsang GB, Pavletic SZ, eds. Chronic graft-versus-host disease: Interdisciplinary
management. First ed. New York, New York: Cambridge University Press, 2009; 124-133.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 42
Arat M, Idilman R, Soydan EA, Soykan I, Erden E, Karayalcin S, Akan H. Ursodeoxycholic acid
treatment in isolated chronic graft-vs.-host disease of the liver. Clinical Transplantation
2005;19:798-803.
Orlando G, Ferrant A, Schots R, Goffette P, Mathijs J, Lemaire J, Danse E, et al. Liver
transplantation for chronic graft-versus-host disease: case report with 10-year follow-up.
Transplant International 2005;18:125-129.
HEPATITIS VIRUSES
Nieters A, Kallinowski B, Brennan P, Ott M, Maynadie M, Benavente Y, Foretova L, et al.
Hepatitis C and risk of lymphoma: results of the European multicenter case-control study
EPILYMPH. Gastroenterology 2006;131:1879-1886.
Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of
lymphoproliferative disorders after treatment for hepatitis C infection. Alimentary Pharmacology
& Therapeutics 2005;21:653-662.
Lok ASF, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50:661-662.
Lalazar G, Rund D, Shouval D. Screening, prevention and treatment of viral hepatitis B
reactivation in patients with haematological malignancies. British Journal of Haematology
2007;136:699-712.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 43
Hui C-K, Cheung WWW, Zhang H-Y, Au W-Y, Yueng Y-H, Leung AYH, Leung N, et al.
Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing
cytotoxic chemotherapy. Gastroenterology 2006;131:59-68.
Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk
and recommendations for prophylaxis and screening among patients with lymphoproliferative
disorders treated with alemtuzumab. British Journal of Haematology 2006;132:3-12.
Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, et al. Effects of
iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in
thalassemia following bone marrow transplantation. Blood 2002;100:17-21.
Shuhart MC, Myerson D, Childs B, Fingeroth JD, Perry JJ, Snyder DS, Spurgeon CL, et al.
Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical
course. Blood 1994;84:3229-3235.
Andreoni KA, Lin JI, Groben PA. Liver transplantation 27 years after bone marrow
transplantation from the same living donor. New England Journal of Medicine 2004;350:26242625.
Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MT, Burns LJ, Davies SM, et al.
Recommended screening and preventive practices for long-term survivors after hematopoietic
cell transplantation: joint recommendations of the European Group for Blood and Marrow
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 44
Transplantation, Center for International Blood and Marrow Transplant Research, and the
American Society for Blood and Marrow Transplantation. Bone Marrow Transplantation
2006;37:249-261.
IRON OVERLOAD
Kamble R, Mims M. Iron-overload in long-term survivors of hematopoietic transplantation.
Bone Marrow Transplantation 2006;37:805-806.
Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C, Galimberti M,
et al. Hepatic iron concentration and total body iron stores in thalassemia major. New England
Journal of Medicine 2000 343:327-331.
Strasser SI, Kowdley KV, Sale GE, McDonald GB. Iron overload in bone marrow transplant
recipients. Bone Marrow Transplant 1998;22:167-173.
Bair S, Spaulding E, Parkkinen J, Shulman HM, Lesnikov V, Beauchamp M, Canonne-Hergaux
F, et al. Transplantation of allogeneic T cells alters iron homeostasis in NOD/SCID mice. Blood
2009;113:1841-1844.
Lucarelli G, Angelucci E, Giardini C, Baronciani D, Galimberti M, Polchi P, Bartolucci M, et al.
Fate of iron stores in thalassaemia after bone-marrow transplantation. Lancet 1993;342:13881391.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
page 45
Muretto P, Angelucci E, Lucarelli G. Reversibility of cirrhosis in patients cured of thalassemia
by bone marrow transplantation. Annals of Internal Medicine 2002;136:667-672.
CANCER IN THE LIVER
Socie G, Deeg HJ: Secondary Malignancies and Other Late Effects. In: Vogelsang GB, Pavletic
SZ, eds. Chronic graft-versus-host disease: Interdisciplinary management. First ed. New York,
New York: Cambridge University Press, 2009; 326-334.
Bhatia S, Louie AD, Bhatia R, O'Donnell MR, Fung H, Kashyap A, Krishnan A, et al. Solid
cancers after bone marrow transplantation. Journal of Clinical Oncology 2001;19:464-471.
FUNGAL ABSCESS
Thaler M, Pastakia B, Shawker TH, O'Leary T, Pizzo PA. Hepatic candidiasis in cancer patients:
the evolving picture of the syndrome. Annals of Internal Medicine 1988;108:88-100.
Oliver MR, Van Voorhis WC, Boeckh M, Mattson D, Bowden RA. Hepatic mucormycosis in a
bone marrow transplant recipient who ingested naturopathic medicine. Clinical Infectious
Diseases 1996;22:521-524.
NODULAR REGENERATIVE HYPERPLASIS
Snover DC, Weisdorf S, Bloomer J, McGlave P, Weisdorf D. Nodular regenerative hyperplasia
of the liver following bone marrow transplantation. Hepatology 1989;9:443-448.
McDonald GB: Complications of hematopoietic cell transplant (ON-LINE VERSION) (Revised 2/13/16)
GALLBLADDER,
page 46
BILIARY DISEASE, AND PANCREATITIS
Teefey SA, Hollister MS, Lee SP, Jacobson AF, Higano CS, Bianco JA, Colacurcio CJ.
Gallbladder sludge formation after bone marrow transplant: sonographic observations. Abdom
Imaging 1994;19:57-60.
Sastry J, Young S, Shaw PJ. Acute pancreatitis due to tacrolimus in a case of allogeneic bone
marrow transplantation. Bone Marrow Transplantation 2004;33:867-868.