Immunosuppression
Immunity, which is ablated by
conditioning before transplantation, returns only
slowly after engraftment. Although B-lymphocyte
function returns after 1-4 months, T-cell immunity
recovers only after 9-12 months or longer. GVHD
(especially chronic) and immunosuppressive
treatments further delay recovery of immune
function. Therefore, patients are at risk for
bacterial, viral, and fungal infections during the
entire first year after BMT and sometimes longer.
Immunizations with protein antigen immediately or
soon after BMT cause antibodies to rise, but only
transiently. In contrast, delaying immunization
until the time when T lymphocytes recover (ie,
6-12 mo after BMT) allows for sustained antibody
production.
Chronic graft versus host
disease
Chronic GVHD occurs at or after
100 days from BMT. Several types exist, including
progressive (ie, developing from acute GVHD), de
novo (ie, without prior acute GVHD), or quiescent
(ie, after previously resolved acute GVHD).
Certain patients, including those who were
transplanted with HLA-nonidentical donors, those
with prior acute GVHD, and those older than 20
years at the time of transplant are more
predisposed than others. Other predictive factors
include the type of GVHD prophylaxis and ongoing
chronic viral infections. Patients who are the
recipients of peripheral blood allografts are at
greater risk for chronic GVHD.
Many organs can be involved,
especially the skin, liver, eyes, mouth, lungs, GI
tract, and neuromuscular system. Histology of
affected skin shows markedly decreased numbers of
Langerhans cells, deposition of lymphocytes, and
immunoglobulin complexes. Liver involvement is
less common than in acute GVHD and usually
reflects cholestatic abnormalities, with
hyperbilirubinemia and, rarely, cirrhosis.
Keratoconjunctivitis sicca also occurs; patients
present with ocular burning, irritation, and
photophobia, and it can be diagnosed by the
Schirmer test for tear production.
Although chronic GVHD can
resemble Sjögren syndrome, the high percentage of
CD8 lymphocytes relative to CD4 cells helps to
differentiate these 2 entities. An uncommon but
particularly severe manifestation is
bronchodilator-resistant obstructive lung disease,
sometimes progressing to bronchiolitis obliterans.
This occurs more commonly in patients previously
treated with methotrexate, those who have
hypogammaglobulinemia, or those who have received
GVHD prophylaxis with methotrexate.
Although gastrointestinal
involvement is less common in chronic than in
acute GVHD, it can result in severe dysphagia,
pain, or weight loss. Very rarely, nephrotic
syndrome, bullous esophagitis, hemolytic anemia,
and unexplained effusions can occur. Cardiac
involvement is distinctly uncommon, although
findings consistent with chronic GVHD have been
identified in the myocardium of some patients, and
complete heart block in an infant, presumably
secondary to chronic GVHD, has been reported.
Thrombocytopenia may occur, and occasionally
autoimmune hemolytic anemia or eosinophilia is
associated.
No specific laboratory test
exists to detect, monitor, or follow chronic GVHD.
However, some patients may have serum evidence of
autoimmunity or altered cytokine production.
Different treatments have had variable success in
chronic GVHD. These treatments include prednisone
in combination with tacrolimus or cyclosporine,
antithymocyte globulin, azathioprine, thalidomide,
clofazimine, and others. For skin involvement,
only psoralen plus ultraviolet light of A
wavelength (PUVA) may be successful; photopheresis
(a derivative method of PUVA in which lymphocytes
are treated with psoralen and ultraviolet light)
may be effective in refractory systemic chronic
GVHD. Artificial tears and/or local retinoic acid
to eyes may alleviate dryness, and sunscreen
lotion can prevent activation of skin GVHD. For
patients with fascial thickening, range of motion
exercises are important to prevent the development
of contractures.
Risks of secondary malignancy after radiation
therapy alone, chemotherapy alone, and combined
chemotherapy and radiation therapy exist. These
risks also apply to patients who have undergone
BMT; whether the risk is higher than in patients
having undergone standard high-dose chemotherapy
and/or radiation therapy has not yet been well
defined. Secondary malignancies, especially
lymphomas, can occur after BMT. One type of
lymphoma, Epstein-Barr virus (EBV) B-cell
lymphoproliferative disease (BLPD), may be fatal
and occurs with the highest frequency in patients
who have received T cell–depleted bone marrow
donor cells. The risk is reported as 0.6% of
patients after allogeneic bone marrow
transplantation (Zutter, 1988). Amplified copies
of the EBV genome reside within lymphocytes.
BLPD can be monoclonal or
polyclonal. Patients with the monoclonal form have
poorer survival rates than patients with the
polyclonal form. Polyclonal EBV
lymphoproliferative disorder may resolve with
suspension or lightening of immunosuppression,
with or without immunoglobulin, acyclovir, or
interferon treatment. However, monoclonal disease
does not respond to such simple measures, and
chemotherapy with or without radiation therapy may
be required. Monoclonal antibody therapy targeting
B-cell antigens such as rituximab (anti-CD20) can
also be efficacious. Survival rates for patients
with monoclonal EBV lymphoproliferative disease
are bleak. In recent years, lymphocyte infusions
from the donor have been associated with dramatic
responses in many patients with BLPD.
Approximately 1-2 cases per 100
exposure-years occur in the first year after bone
marrow transplantation (Kolb, 1992). In addition
to lymphoid malignancies, solid tumors occur.
Curtis et al (1997) reported a high rate of
observed malignancies compared to what was
expected, primarily in patients who were younger
than 10 years at the time of treatment, those who
received total body irradiation (TBI), and those
who developed GVHD. Skin and oropharyngeal cancers
are especially common.
The endocrine system suffers a
disproportionate toll after BMT; gonad, growth,
and thyroid failure are the most common sequelae.
These disturbances are often underappreciated, and
yet they seriously disrupt the quality of life of
otherwise healthy patients.
Growth problems
Growth problems are more common
and severe in patients receiving TBI-containing
regimens. Patients with neuroblastoma receiving
autologous transplants that include TBI often have
more persistent and severe growth failure than do
those treated for leukemia, and these patients are
less likely to catch up or to respond to growth
hormone treatment, probably because of radiation
therapy to the spine and pelvis at an early age.
Gonad failure
Ovarian and testicular function
invariably is affected by high-dose alkylator and
by radiation therapy, at least for varying
periods. The degree and the duration of gonadal
failure depend on the dose of radiation therapy
received and at which age it is received. Pubertal
and postpubertal girls at the time of transplant
almost always develop ovarian failure manifested
by high luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) levels with or
without decreased estrogen levels. These girls are
at risk for early osteoporosis, bone fractures,
lipid disorders, and atherosclerotic heart
disease. Osteoporosis risk is potentiated by
associated use of steroids and radiotherapy.
Women with ovarian failure after
BMT respond well to estrogen replacement. The
known risks of estrogen (ie, predisposition to
endometrial and breast cancer) must be weighed
against those of bone and heart disease. The role
of bisphosphonates to decrease the development of
osteopenia as well as to reduce the risk of
fractures in patients with osteopenia may be
promising for patients undergoing chemotherapy but
has not yet been systematically studied in BMT
patients.
Younger girls have an
approximately 50% chance of developing ovarian
failure, while older girls and women have a higher
rate of ovarian failure (approximately 90%),
depending on the dose of radiation used in the
preparative regimen. Younger girls are less
sensitive to the risk of ovarian failure than are
older girls and women. For example, Sarafoglou
(1997) showed that 50% of prepubertal girls
progress to normal puberty with normal onset of
menses and normal estrogen levels. However, many
of these patients continue to have high LH and FSH
levels, representing subclinical early ovarian
failure. Whether prepubertal women progress to
regain normal fertility and what percentage
proceeds to normal fertility is not yet known nor
is the duration of fertility once achieved.
Girls and women who regain their
reproductive potential and who become pregnant
after BMT have a high risk for pregnancy
complications, including spontaneous abortion,
premature deliveries, and low–birth weight
infants. However, infant congenital anomalies are
not increased. Infant risk for malignancy also is
not increased. Conversely, women partners of men
who have undergone and survived BMT do not have
high risk of pregnancy complications. Ninety
percent of prepubertal boys undergo puberty
normally and maintain testosterone levels within
the reference range. The resistance of boys'
gonads to chemotherapy and radiation therapy is
also a function of increased numbers of Sertoli
cells in prepubertal boys compared to that in
postpubertal boys and men. However, postpubertal
men may develop testosterone deficiency. The male
menopause is a less recognized syndrome than its
counterpart in females but is likely to encompass
medical and psychosocial complications.
Other hormone abnormalities
Other hormone abnormalities
include thyroid dysfunction with decreased thyroid
hormone production and increased
thyroid-stimulating hormone (TSH). These patients
may present with signs of hypothyroidism and may
require replacement therapy. The authors have
recently found that some patients may also develop
pineal gland involvement.
A major concern after BMT is
long-term residual damage to organs from
chemotherapy and radiation therapy. Because tissue
damage due to chemoradiation may result in
permanent organ damage, many patients are likely
to experience long-term organ damage after
transplantation.
Pulmonary abnormalities
Few children surviving BMT have
clinically significant pulmonary symptoms, yet
25-50% of surviving children have abnormal
pulmonary function test results. Etiologic factors
for pulmonary restrictive syndrome are
chemotherapy, scoliosis, kyphosis, thoracotomy,
post-BMT interstitial pneumonitis, and GVHD.
Pulmonary restrictive syndrome is much more common
in patients who were treated with TBI.
Cytomegalovirus (CMV) pneumonitis is reported to
have a mortality rate of approximately 30-40%.
This rate may decrease with the advent of better
screening for CMV activation and with improved
antiviral agents (de Medeiros, 2000). Interstitial
pneumonitis occurs in 20-50% of patients after
allogeneic BMT and in 10% of patients treated with
autologous BMT. It generally occurs within the
first 4 months after BMT, but it can occur later.
Italian investigators found that
at 6 years after transplantation the incidence of
pneumopathy was 10%. A highly statistically
significant correlation with type of BMT was
found; incidence was much higher with mismatched
or unrelated donors. Pneumocystis carinii
pneumonia (PCP) prophylaxis was used, but it bore
no relationship to underlying disease,
conditioning regimen, use of TBI, or whether the
patient was transplanted in a large or small BMT
center. In contrast to this study, most
investigators have noted an association between
the risk for pneumopathy and the total dose, dose
rate, and dose fractionation scheme of TBI. Others
have found that rates are much lower if patients
undergo transplantation early in the course of
their disease and, therefore, have received little
prior therapy.
Cardiac abnormalities
The major risks of long-term
cardiotoxicity relate to treatment prior to the
BMT, in particular, anthracyclines, ablative-dose
Cytoxan (ie, dose >150 mg/kg), chest radiation
therapy, TBI (especially if not fractionated), and
high-dose steroids. Most patients have some degree
of cardiac dysfunction during and immediately
after BMT, and as many as 50% have persistent
abnormalities. However, these abnormalities
usually are subclinical and rarely limit the
patient's quality of life.
Cardiac dysfunction may not be
identified by conventional testing at rest. For
example, Larsen et al (1992) found significant
cardiotoxicity by exercise stress echocardiography
in 50% of his pediatric patients 7 years after BMT.
Abnormalities included decreased exercise time,
decreased maximal oxygen consumption, and
decreased ventilatory anaerobic thresholds. In
this same population, only 10% manifested
abnormalities after echocardiography at rest and
none manifested abnormalities on ECG alone. The
degree of cardiac abnormalities varied by
underlying disease.
Patients who received little or
no therapy before BMT (eg, those with aplastic
anemia) had significantly fewer abnormalities than
those who had been heavily pretreated, suggesting
that the damaging effects may relate to cumulative
chemotherapy and radiation toxicity rather than to
the BMT itself. However, almost all BMT regimens
contain ablative-dose Cytoxan, which can cause
hemorrhagic myocarditis, especially in patients
with preexisting cardiac injury. Radiation therapy
further enhances this toxicity.
Cardiotoxicity increases over
time, even without further therapy. Thus, Larsen
(1992) showed that children who survived BMT for
fewer than 3 years had fewer abnormalities than
those who had survived for more than 3 years, even
when treated with similar preparative regimens.
The authors speculate that this discrepancy over
time is related to loss of reserve of heart
muscle, early progression of atherosclerosis, or
even chronic GVHD.
Recently, heart attack has been
reported to be a potential manifestation of GVHD
after BMT. Myocardial GVHD is exceedingly uncommon
(Kupari, 1990). Hormonal changes may predispose to
heart disease. Almost all postpubertal women and
one half of prepubertal girls develop estrogen
deficiency and lose the normally protective
effects of estrogen against coronary artery
disease. Deficiency of estrogen accelerates
coronary artery disease. Trials with
chemopreventive agents such as dexrazoxane and
amifostine to prevent chemotherapy-induced
cardiotoxicity are under consideration, as are
trials with afterload-reducing agents to prevent
progression of cardiomyopathy.
Renal complications
A study at the University of
Florida BMT unit showed that most children
undergoing BMT have normal renal function years
after treatment. Of children studied for more than
6 years from the time of transplantation, 89% had
normal renal function (Kumar, 1996). The other 11%
were asymptomatic but were found to have
hemofiltration abnormalities or hyposthenuria
(9/11) on testing.
Dental, cranial, and facial
abnormalities
In one recent study of 27
patients aged 1-18 years who had undergone BMT, a
high rate of dental abnormalities was observed.
These abnormalities included serious gingivitis in
60% of patients, parodontal involvement in 4%,
dentofacial abnormalities in 56%, tooth agenesis
in 63%, and dental root hypoplasia in 33%.
Patients who received or did not
receive radiation therapy were affected equally.
Younger age at time of BMT was a risk factor, and
causative factors included drug and radiation
therapy toxicity, difficulty in maintaining
adequate active oral hygiene, frequency of oral
mucosa bacterial infections, and the xerostomia
occurring in most patients after BMT. Other
investigators have shown a similarly high rate of
dental abnormalities in the long-term follow-up
care of children after BMT. For example, Dahlof
(1997) demonstrated that salivary secretion was
decreased in 26 patients up to 4 years after
having undergone BMT, especially in those who had
received TBI.
The decreased salivary secretion
resolved within 4 years in most patients
conditioned with chemotherapy but persisted in all
of those who received TBI as part of the
preparative regimen, suggesting that the damage to
salivary glands may be permanent after radiation
treatment. Patients who had impaired salivary
secretion also had concomitant increased counts of
mutans streptococci and lactobacilli compared to
those who had normal salivary flow and compared to
healthy age- and sex-matched children. However,
despite these abnormalities, children who received
chemotherapy alone, chemotherapy plus radiation
therapy, and healthy children had similar rates of
dental caries. Thus, despite abnormalities,
patients may not develop serious problems with
caries if sufficient care is taken with oral
hygiene.
Ophthalmic abnormalities
Vision defects are common in
children after BMT. In a study of 100 children
surviving more than 5 years after BMT, almost one
third had long-term vision defects (Ng, 1999).
The most common of these were
subcapsular posterior or other cataracts secondary
to radiation and or steroid treatment. The second
most common problem was dry eye syndrome, which
can be a precursor or early sign of chronic GVHD.
Other less frequent eye complications included
retinal hemorrhages and panuveitis. In contrast,
early after BMT, cortical blindness and
microvascular retinopathy are the 2 main causes of
deteriorating vision. Cyclosporine has been
implicated in the pathogenesis of these problems.
Usually, exclusion of organic brain disease,
meningitis, and encephalitis and performance of
MRI scans and funduscopic examinations are
sufficient to provide a diagnosis. However, in
some patients, electroretinograms and visually
evoked cortical potentials may be necessary to
establish the diagnosis of retinal damage.
Diagnostic tests include
Schirmer tear production and function and corneal
microscopy to detect lymphocyte deposition.
Aural abnormalities
Hearing abnormalities are very
common sequelae of children with neuroblastoma who
survive more than 5 years after transplant.
Osteopathic changes
Osteonecrosis, osteoporosis, and
avascular necrosis of the hip or other joints or
bones can occur in long-term survivors and are
secondary to high-dose steroids, radiation
therapy, and estrogen depletion. A review of 77
patients with avascular necrosis revealed the
following risk factors: acute or chronic GVHD,
patients older than 16 years at time of
transplant, and underlying diagnosis of aplastic
anemia or of acute leukemia. Patients who develop
aseptic necrosis after BMT respond well to joint
replacement when indicated.
