++
Transplant-related complications are those resulting from undergoing
hematopoietic cell transplantation (HCT), not from the underlying disease
process. Transplant-related complications include (1) regimen-related
toxicity, (2) infections, and (3) complications associated with
alloimmune T cells.
+++
Non-Infectious Regimen-Related Toxicity
++
Regimen-related toxicities typically occur within the first month
after myeloablative conditioning, and include cytopenias and organ damage.
Each of these manifests differently in the immediate transplant
period versus long-term sequelae, which are discussed separately below.
More intense conditioning regimens also are associated with greater
risk for infection, which is also affected by the prolonged period
of immune reconstitution following allogeneic grafts. The complications
of allogeneic HCT that may occur irrespective of the intensity of
the conditioning regimen include rejection, graft-versus-host disease
(GVHD) and hemolysis.
++
The likelihood of developing transplant-related complications
depends on patient age, the intensity of the preparative regimen,
the type and stage of the underlying disease, and the presence of
comorbidities.
++
High-dose cytotoxic chemotherapy with or without doses of total
body irradiation (TBI) exceeding 6 Gy may severely disrupt mucosal
integrity and homeostatic mechanisms, and has the potential to cause
regimen-related toxicity (RRT) in the skin, gastrointestinal tract,
liver, bladder, lung, heart, kidney, and nervous system. RRT occurs
predominantly within the first 3 to 4 weeks after conditioning and
is more common after myeloablative than nonmyeloablative conditioning.32-37 RRT
increases the risk for opportunistic infection.32-37 that
is already high because of concomitant profound immunosuppression
and regimen-related cytopenias. This section will focus on the noninfectious
complications of individual organs specifically attributable to
conditioning toxicity. Opportunistic infection or GVHD as etiologies
for organ dysfunction must strongly be considered in the differential
before making a diagnosis of RRT.
++
Reconstitution of hematopoiesis occurs in an orderly pattern;
in general, neutrophil recovery occurs first, followed by recovery
of platelets and red blood cells. Hematopoietic reconstitution varies
according to the type of HSC product, being earlier after peripheral blood
stem cells (PBSC) grafts and later after umbilical cord blood (UCB)
grafts, relative to marrow grafts. Transfusions of 1500 to 3000 cGy irradiated
platelets and red blood cells usually are needed to support hematopoietic function
until hematopoiesis recovers. Transfusion of red blood cells should
be determined by the clinical condition of the patient, including
hemodynamic stability and presence of active hemorrhage. Red blood
cell transfusions generally are indicated when the hemoglobin falls
below 8 g/dL. Platelet transfusions are indicated when
the platelet count falls below 10,000 cells/μL
to minimize the risk for spontaneous bleeding.33 Patients
that have become alloimmunized to platelet antigens demonstrate poor
response to platelet transfusions and may achieve higher platelet
counts by limiting the number of donor exposures, depleting transfused
platelets of leukocytes, controlling fever or disseminated intravascular
coagulation, use of platelet products that are less than 48 hours old,
or use of nonpooled (single-donor) platelets or HLA-matched platelets.34
++
Precautions should be taken in preparation of blood products
for transfusion into HCT patients because passenger lymphocytes
pose a risk for generating GVHD. Except for the stem cell graft,
all other components should be irradiated at a dose of 1500 to 3000
cGy to eliminate contaminating lymphocytes. Depletion of leukocytes
or use of blood components that test seronegative for CMV are equally
effective for prevention of CMV transmission to CMV-seronegative
recipients.35 Removal of white blood cells from
platelet and red blood cell products also decreases the risk for
alloimmunization of the patient.36
++
Generalized skin erythema is common after doses of TBI exceeding
12 Gy but is self-limiting and rarely associated with skin breakdown.
Regimens that contain cytosine arabinoside (Ara-C), thiotepa, busulfan,
etoposide, and carmustine (BCNU) may also cause erythema. Hyperpigmentation
typically follows the inflammatory dermatitis with skin folds often
being particularly noticeable. Skin biopsies during the first 3
weeks after transplant often show nonspecific inflammatory changes
irrespective of cause, making them usually unhelpful in distinguishing
between RRT, drug allergies or acute GVHD.
++
Most patients who receive intensive conditioning regimens develop
mucositis.37,38 Symptoms include inflammation,
desquamation, and edema of the oral and pharyngeal epithelial tissue
that typically presents within the first several days after HCT
and usually resolves by the third week after HCT. Damage to the
mucosa of the lower GI tract results in secretory diarrhea, crampy
abdominal pain, and anorexia, and facilitates translocation of intestinal
bacteria with sepsis.39 Anorexia, nausea, or other
intestinal symptoms that persist after day 21 are more likely to
be caused by graft-versus-host disease (GVHD) or infection. Severe
mucositis places patients at risk for aspiration, and occasionally airway
compromise, indicating the need for endotracheal intubation. Damage
to the mucosa of the lower GI tract results in secretory diarrhea,
crampy abdominal pain, and anorexia, and facilitates translocation
of intestinal bacteria with sepsis.39 The combination
of mucositis, thrombocytopenia, and severe retching may result in
a Mallory-Weiss tear, or esophageal hematoma.40 The
latter condition may have associated symptoms of dysphagia and retrosternal
pain, and can be diagnosed by CT scan.
++
Mucositis is treated supportively with administration of hyperalimentation
and intravenous fluids to provide calories and maintain water balance,
and intravenous narcotics to control pain. Octreotide or loperamide
may be used if diarrhea is severe.41 It is important
to recognize that an iatrogenic narcotic bowel syndrome, characterized
by abdominal pain and bowel dilatation, may be a side effect of
efforts to control painful symptoms of mucositis or liver toxicity.42 Esophageal
bleeding conditions are treated supportively with transfusions to
maintain platelet counts at more than 60,000 per µL and optimal
management of emesis.
+++
Hepatic Sinusoidal
Obstruction Syndrome (SOS)
++
Previously called veno-occlusive disease, sinusoidal-obstruction
syndrome (SOS) is now the preferred term because it more correctly characterizes
the underlying histopathology. Hepatic sinusoidal obstruction syndrome
(previously called veno-occlusive disease) develops in 10% to
60% of patients and is a clinical diagnosis based on the
triad of tender hepatomegaly, jaundice, and unexplained weight gain
usually within 30 days after HCT and in the absence of other explanations
for these symptoms and signs.43,44 It is more likely to
be severe in patients with cirrhosis or fibrosis of the liver, or
those with a history of hepatitis, liver irradiation (>12 Gy), or chemotherapy-induced
SOS. Once SOS is established, mathematical models can be used to predict
prognosis, based on rates of increase in serum bilirubin and weight
within the first 2 weeks after transplantation. The treatment for the
70% to 85% of patients who are predicted to have
a mild or moderate course is largely supportive, with attention
to management of sodium and water balance to avoid fluid overload.
++
Pulmonary complications occur in 40% to 60% of
patients after HCT.45 Noninfectious pulmonary problems
that may occur within 30 days from the transplant include idiopathic
pneumonia syndrome (IPS), pulmonary hemorrhage, pulmonary edema
due to excessive sodium and fluid administration or associated with
sinusoidal-obstruction syndrome (SOS), or acute cardiomyopathy induced
by cyclophosphamide, and sepsis with adult respiratory distress
syndrome (ARDS).46,47 These complications occur
more frequently in older patients, those who receive higher-dose
conditioning regimens, and those with allogeneic donors, particularly
HLA-disparate donors. Although the incidence of life-threatening
pulmonary infections has decreased over the past decade because
of the introduction of routine antimicrobial prophylaxis, pulmonary complications
continue to be a leading cause of death.
++
Cardiac complications related to chemotherapy or radiation occur
in 5% to 10% of patients after HCT but death from
cardiac failure is uncommon.48 Cardiac injury with
hemorrhagic myocardial necrosis is a rare but known adverse effect
of high-dose cyclophosphamide, one of the most commonly used chemotherapy agents
in conditioning regimen. Risk factors for cyclophosphamide cardiotoxicity
include doses exceeding 200 mg/kg, an underlying diagnosis
of lymphoma, prior radiation to the mediastinum or left chest wall,
older age, and prior abnormal cardiac ejection fraction. Patients
who had prior cumulative anthracycline exposures of 550 mg/m2 doxorubicin
equivalents are at an increased risk for developing heart failure.49
++
Acute renal failure (ARF), defined by doubling of baseline serum
creatinine, occurs in 30% to 50% of all patients
during the first 100 days after hematopoietic cell transplantation
(HCT), and most often during the first 10 to 30 days.50-52 Occasionally,
ARF develops during conditioning or infusion of HSC, as a consequence
of tumor or red-cell lysis. ARF occurs most frequently in the setting
of SOS, and is characterized by low urinary sodium concentration
and high blood urea nitrogen to creatinine ratio, similar to the
hepatorenal syndrome. Renal hypoperfusion, caused by acute hemorrhage,
sepsis, or high-volume diarrhea, may result in ARF. Nephrotoxic
drugs such as cyclosporine, tacrolimus, all amphothericin products,
and aminoglycosides frequently cause renal insufficiency. Thrombotic
microangiopathy, endothelial damage caused by chemoradiotherapy,
cyclosporine, or tacrolimus, occurs in 5% to 20% of
patients, more frequently in allograft recipients. The hallmark
of thrombotic microangiopathy is RBC fragmentation (schistocytes)
associated with increased RBC turnover (increased reticulocytes;
elevations of serum lactate dehydrogenase [LDH] and
indirect bilirubin) without evidence for immune-mediated hemolysis
or disseminated intravascular coagulation. The syndrome ranges from
subclinical hemolysis to life-threatening hemolytic uremic syndrome
or TTP.53,54
++
Hypertension develops in approximately 60% of patients
after HCT, more often in patients given cyclosporine for GVHD prophylaxis. Glucocorticoid
therapy also contributes to the development of hypertension. Uncontrolled hypertension
may lead to fatal intracerebral bleeding in thrombocytopenic patients.
Therefore, hypertension should be anticipated and controlled medically. Most
patients respond to conventional antihypertensive therapy, such
as a calcium-channel blocker, angiotensin-converting enzyme inhibitor,
or beta-blocker. Correction of hypomagnesemia, which often confounds
cyclosporine therapy, may improve control of hypertension.55
++
High-dose cyclophosphamide is commonly used for conditioning
and one of its toxic metabolites, acrolein, accumulates in the urine and
may cause a hemorrhagic chemical cystitis during the conditioning
regimen or later after HCT.56,57 Measures to prevent hemorrhagic
cystitis include aggressive fluid hydration to increase urine volume
that dilutes and minimizes contact of acrolein with the mucosa,
and administration of the drug mesna, which provides free thiol
groups to detoxify acrolein.58 Viral infections,
particularly adenovirus and BK virus, also have been implicated
in the development of hemorrhagic cystitis and the diagnosis is
established by viral culture or PCR test of a urine sample.59 Unless there
is evidence of disseminated infection, viral cystitis is managed
with supportive therapy, including aggressive hydration and platelet
transfusions.
+++
Central Nervous
System
++
Noninfectious complications include, cerebrovascular events,
and encephalopathies because of metabolic, toxic, and immune-mediated
causes. Focal symptoms are more indicative of infectious or cerebrovascular
mechanisms, whereas diffuse symptoms such as delirium or coma may
have metabolic causes. Fever is not necessarily associated with
central nervous system (CNS) infections. Infection should be considered
as the cause of any neurologic symptom and should prompt evaluation, including
obtaining CT or magnetic resonance imaging (MRI) scans of the head
and a sample of cerebrospinal fluid for appropriate cultures, cytochemistry
stains, and PCR tests should be obtained.60
++
A rare syndrome of encephalopathy associated with hyperammonemia
has been reported in a small number of patients after HCT.61 Plasma
ammonia levels may exceed 200 mM/L without other chemical
evidence of liver failure. Contributing factors may include the hypercatabolic
state induced by conditioning, glucocorticoids, or sepsis, and exposure
to high nitrogen loads from total parenteral nutrition, or intestinal
hemorrhage.
++
Cyclosporine or tacrolimus and glucocoricoids can cause a range
of neurotoxicities.62,63 Essential tremor develops
in most patients. Seizures have been reported in up to 6% of
patients and may present in association with headaches, tremor,
or visual disturbances. Seizures should be managed with anticonvulsant
therapy and cessation of the drug if possible, or if not, substitution
of one agent for the other. A unique and usually reversible syndrome
of cortical blindness has been reported as a complication of cyclosporine
treatment; hypertension and hypomagnesemia are thought to be predisposing factors.64 Toxicity
as a result of calcineurin inhibitor therapy may occur with “therapeutic” drug
levels and clinical suspicion is often confirmed by MRI scans that
show multifocal areas of signal hyperintensity on T2 and FLAIR sequences,
most often in the occipital lobe white matter. Glucocorticoid therapy
may be associated with psychosis, mania or delirium in a dose-dependent
fashion.65