Introduction: HCT recipients, 85% of those who were alive

Introduction:
Hematologic
stem cell transplant (HCT) is potentially a curative treatment option for
variety of hematologic diseases. Advances in the field of HCT over the past
decade due to safer conditioning regimens, better post-transplant supportive
care, and alternative graft sources has markedly increased the number of
transplants performed leading to an increase in long-term survivors (Figure 1).
This success has also brought the recognition of long-term health impact of HCTsuch
as cardiopulmonary compromise, musculoskeletal disorders, endocrinopathies, and
subsequent malignancies. These
complications have the potential for substantial morbidity and mortality and negatively
impact quality of life among HCT survivors.  Continued lifelong surveillance for
prevention, early detection and timely treatment of late complications is critical
to optimize long-term outcomes. This review will describe the burden of
morbidity experienced by HCT survivors and provide an overview of current
follow-up recommendations.

Long-term survival after HCT: The
prospect for long-term survival is excellent for 2-year survivors of allogeneic
HCT. Based on Center for International Blood and Marrow Registery (CIBMTR)
retrospective study of 10,632 allogeneic HCT recipients, 85% of those who were
alive and disease free 2 years after allogeneic HCT are expected to become a
long-term survivor. However, life expectancy
of HCT survivors continues to lag behind that of age- and gender-matched
general population for at least 15 to 20 years after HCT. Disease relapse is
the most common cause of late death among patients with malignant
disorders.   In most cases recurrent
malignancy occurs within the first 2 years after the transplant, with few
occurring more than 5 years after the transplant. Therefore,
intense surveillance for recurrent malignancy after 5 years can be reduced. Following
disease relapse, other causes of late deaths 
are chronic graft versus host disease (GVHD), organ toxicity, late
infections and secondary cancers (Figure 2).

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Organ
toxicity: The following highlights the most common organ
toxicity seen after HCT and recommendations for screening and prevention based
on Recommended Screening
and Preventive Practices

Cardiovascular
complications-HCT survivors have
an increased risk for cardiovascular
complications such as coronary artery disease, peripheral arterial disease and
cardiomyopathy. There is a 2-fold increase in risk of cardiovascular death
among HCT survivors compared with the general population. Early onset
cardiovascular events are primarily due to accelerated atherosclerosis due to
radiation (pre-transplant or total body irradiation as a part of transplant
conditioning regimen). HCT
survivors also have a high prevalence of metabolic syndrome which represents a
cluster of risk conditions associated with premature coronary artery disease.

Education and counseling on “heart Healthy” lifestyle
including a regular exercise, healthy dietary habits and screening for
dyslipidemia, diabetes and hypertension should be recommended to all HCT
survivors. Routine clinical assessment of cardiovascular risk factors is
strongly recommended at 12 months post-transplant and annually afterwards. In asymptomatic
adults without any cardiac risk factors, cardiac imaging tests are not
recommended. More frequent assessments and if clinically appropriate, further cardiac
evaluations may be indicated in patients at high-risk for cardiac complications
including patients who had mediastinal radiation, patients with amyloidosis,
and those with pre-existing cardiac and vascular complications.

Endocrine
Complications–Thyroid dysfunction Thyroid dysfunction is among the most common
long-term endocrine complications post autologous and allogeneic HCT. Total body radiation (TBI), younger
age at transplant and presence of GVHD are the most recognized risk factors for
thyroid dysfunction after HCT. Based on international blood and marrow
transplant guidelines, thyroid function assessment is recommended yearly after HCTindefinitely
or in presence of relevant symptoms.

Gonadal
dysfunction is
very common in HCT, recipients affecting as high as 92% for males and 99% for
females. Age at transplantation, gender, pre-transplant therapy and intensity
of conditioning regimen (especially high dose irradiation and busulfan) influence
the degree of gonadal dysfunction. Women who were post-pubertal at the
time of transplantation should have clinical and endocrinologic gonadal
assessment 1 year after HCT. Subsequent assessment should be guided by
menopausal status. Gonadal
function in men (FSH, LH, and testosterone) is warranted by symptoms. 

Skeletal
complications-Loss
of bone density is a well-known complication of HCT with reported incidence
rates as high as 25% for osteoporosis and 50% for osteopenia in some studies. Older
age, female gender, low body mass index, physical inactivity and prolonged
systemic corticosteroids exposure (? 5 mg prednisone equivalent daily for >3
months) are well-recognized risk factors. Dual photon densitometry (DEXA scan)
for adult women, all allogeneic HCT recipients, and patients at high risk of
bone loss after HCT is recommended one year post HCT. Subsequent testing is
determined by the findings of first DEXA Scan or to assess therapy response.
Education and counseling of HCT survivors about physical activity, vitamin D
and calcium supplementation is highly recommended to prevent bone density loss.

Avascular
necrosis (ANV) of the bone is another debilitating skeletal compilation post
allogeneic HCT with a cumulative incidence of 3% to 10% at 5 years after HCT.
In addition to risk factors for osteoporosis , TBI as a part of conditioning
regimen has been associated with AVN. Joint pain and discomfort is the first
manifestation of AVN. Most commonly affected joints are hips (more than 80% of
cases), knees and wrists. Standard imaging (X-ray) may not detect the
abnormality until late stages of the disease. Thus, MRI imaging in patients
with persistent joint pain with higher risk of AVN for early detection and
prompt referral to an orthopedic specialist is recommended.

Ocular complications- Cataract and sicca syndrome are amongst the most common
ocular complications after HCT.TBI as sequelae from the preparative regimen and
prolonged use of corticosteroids after.
The median time to develop cataracts
after transplant ranges from 2 to 5 years. An annual eye exam with slit lamp
examination is recommended for all patients who have had an allogeneic HCT and
for those who are at risk of cataracts.

Oral
Complications- The
oral cavity is one of the sites most commonly affected by chronic GVHD after
allogeneic HCT. Impact of chronic GVHD on salivary glands lead to qualitative
and quantitative salivary changes (dry mouth) leading to development of dental
caries. Patients with a history of oral chronic GVHD are at risk of development
of intra-oral malignancy (especially, squamous cell oral cancer). Routine
clinical oral assessment and dental health examinations are strongly recommended
6 months and 1 year post-transplant
and annually afterwards. More frequent
oral examination (every 6 months)is required in patients with chronic GVHD,
oral mucosal lichenoid lesions, and/or a history of
Fanconi’s anemia. Patients should be encouraged to carry out effective oral hygiene,
avoid smoking and chewing tobacco, and perform oral self-inspection.Chronic
GVHD, a potentially life-threatening post-transplant complication, occurs in
approximately 40% to 70% of recipients of allogeneic HCT.  It is an immune response of the donor T cells
against recipient tissues. Chronic GVHD is not only a major cause of
non-relapse mortality, it can lead to significant morbidity and decline in
health-related quality of life. Thus, ongoing surveillance and early
recognition of signs and symptoms of chronic GVHD is critical to
optimize long-term outcomes (Table 1). When signs of chronic GVHD appears
collaboration with the transplant center to confirm diagnosis and management is
necessary.

Post-HCT
vaccination: Levels
of antibodies to diseases that can be prevented by vaccination decrease significantly within the first few years
after HCT. Therefore,
patients should be routinely revaccinated after transplant until they regain
immune competence. Table 2 outlines the vaccination schedule
for autologous and allogeneic HCT recipients based on international consensus
guidelines. Live vaccinations including (Measles-mumps-rubella)
MMR and varicella-zoster vaccination should not be administered to individuals
with active GVHD,on immunosuppressanttherapy and patients less than 2 years
post HCT.It is strongly recommended that
the patient’s family members and close contacts be current on vaccinations to
help protect the patient from exposure to infectious diseases.Patient’s family
members or close contacts can safely receive inactivated vaccines according to
the recommended Centers for Disease Control and Prevention (CDC) schedule.

 Secondary
malignancies including post-transplant lymphoproliferative disorder (PTLD),
myelodysplasia (MDS), acute myeloid leukemia (AML), and solid tumors are
well established complicationsin long-term HCT survivors. Risk factors
associated with the development of secondary cancers include genetic
predispositions of patient to develop cancer, older age at the time of
transplant, use of TBI, chronic GVHD, and prolonged immunosuppressive therapy. MDS,
AML and PTLD develop relatively early in the post-transplant period. Solid
tumors have a longer latency time. Survivors of HCT have a 2 to
3-fold increased risk of developing subsequent solid cancers compared with the general
population. Large retrospective
series have estimated the cumulative incidence rates of secondary solid tumors
at 1 to 2 percent at 10 years and 3 to 5 percent at 20 years after allogeneic
HCT. Cancers that occur at increased frequency include skin cancers (squamous
cell, basal cell, and malignant melanoma), cancers of the buccal cavity, liver,
central nervous system, thyroid, bone, and connective tissue. Therefore, it
is important to notify HCT survivors regarding an increased risk of
developing a malignancy following HCT and encourage in healthy behaviors
(healthy diet, exercise, smoke cessation) and encourage report of any
concerning symptoms. It is also important to encourage patients to reduce sun
exposure through use of high SPF sunscreens or skin coverage. In addition to a
routine physical examination, annual complete skin examination and dental
evaluation to monitor for the development of skin and oral cancers is
recommended.  More frequent oral
examination is required in patients with chronic GVHD, oral mucosal lichenoid
lesions, and/or a history of Fanconi’s anemia.
 Female HCT survivors screening for breast cancer should start at age 40
years. For patients who have received total body or chest irradiation, breast
cancer screening begins eight years after radiation or at age 25 years,
whichever occurs later.  Routine
age-appropriate cancer surveillance for other secondary malignancies should
follow the recommendations outlined under the General Health and Preventive
Screening section.