Recommended Screening and Preventive Practices for Long-term Survivors after Hematopoietic Cell Transplantation: Joint Recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation

Introduction 

More than 40000 hematopoietic cell transplants (HCTs) are performed worldwide each year. With improvements in transplant technology, more transplant recipients now survive free of the disease for which they were transplanted. There are tens of thousands of HCT survivors alive today.

Although HCT is associated with considerable early morbidity and mortality, long-term survivors generally enjoy good health. This notwithstanding, there are sequelae that can cause substantial morbidity. Optimizing outcomes through prevention or early detection of complications and mitigation of disability are high priorities. Many survivors are no longer under the care of transplant centers, and many community health care providers may be unfamiliar with health matters relevant to HCT. The purpose of these recommendations is to offer care providers suggested screening and prevention practices for autologous and allogeneic HCT survivors. Our goal is to provide an overview of the late complications faced by transplant recipients and provide reasonable recommendations for care. Complications of the immediate post-HCT period are extensively reviewed elsewhere [1, 2, 3, 4, 5, 6]. Similarly, because of variability in the anticipated course of diseases for which transplantation is performed, this document does not include specific recommendations regarding disease follow-up. Comprehensive guidelines for follow-up of pediatric cancer survivors recently developed by the Children’s Oncology Group can be found at http://www.survivorshipguidelines.org.

The following recommended screening and preventive practices were developed by a consensus panel formed by members of the Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Bone Marrow Transplantation (ASBMT). These recommendations focus on risks faced by patients beyond 6 months following transplantation. Summary recommendations can be found in Table 1, Table 2. These recommendations are not all based on evidence derived from randomized or other controlled trials, since in most cases preventive practices have not been subjected to such trials. Most recommendations derive from studies that have identified specific complications in long-term survivors and the risk factors associated with them. As such, they represent sensible practices to optimize outcomes. The recommendations should not be judged as mandatory for all recipients; good medical practice and judgment dictate that certain recommendations may not be applicable or may even be contraindicated in individual patients or groups of patients.

Table 1. EBMT-CIBMTR-ASBMT Summary Recommendations for Screening and Prevention in Long-Term HCT Survivors

	Tissues/Organs	Late Complications	Risk Factors	Monitoring Tests and Preventive Measures
	Immune system	Infections	Donor source HLA disparity T-cell depletion Graft-versus-host disease (GVHD) Venous access devices	Antibiotic prophylaxis targeting encapsulated organisms for duration of immunosuppressive therapy for cGVHD. Some experts recommend antifungal prophylaxis for those receiving chronic corticosteroids Administration of prophylactic antibiotics for oral procedures should follow American Heart Association guidelines for endocarditis prophylaxis PCP prophylaxis for initial 6 months for all HCT recipients, or duration of immunosuppressive therapy to treat or prevent cGVHD Some experts recommend continued CMV antigen or PCR testing for allogeneic recipients with chronic immunosuppression or chronic GVHD. Some experts recommend prophylaxis for HSV in patients receiving chronic immunosuppression for cGVHD Immunizations per CDC or EBMT guidelines initiated at 1 y after HCT. Delayed initiation beyond 1 y may be considered in situations where recipients are unlikely to respond
	Oral	Sicca syndrome Caries	GVHD Radiotherapy	Dental assessment at 6-12 mo; individualized follow-up schedule thereafter according to dental professional. Subsequent dental/oral follow-up care should occur at least annually Particular attention to intraoral malignancy evaluation in cGVHD patients and recipients of radiotherapy
	Liver	GVHD Viral hepatitis Iron overload	Cumulative transfusion exposure	Liver function testing (LFT) every 3-6 months in first year, then individualized, but at least yearly Monitor HbsAg and viral load by PCR for patients with known hepatitis B or C, with liver and infectious disease specialist consultation Liver biopsy to assess cirrhosis should be considered for those with chronic hepatitis C infection after 8-10 y Serum ferritin at 1 y after transplant, with consideration of confirmatory liver biopsy for abnormal results based upon magnitude of elevation and clinical context. Subsequent monitoring is suggested for patients with elevated LFTs, continued RBC transfusions, or presence of hepatitis C infection
	Muscle and fascia	Myopathy Myositis/fasciitis	Corticosteroids GVHD	Frequent (monthly) clinical screening for corticosteroid myopathy Physical therapy consultation for patients with prolonged corticosteroid exposure, fasciitis, or sclerodermatous GVHD may minimize loss of function
	Respiratory	Interstitial pneumonitis Bronchiolitis obliterans Chronic obstructive disease	Intensive conditioning regimen Radiation exposure Infectious agents GVHD	Clinical assessment for all patients at 6 mo, 1 y, and annually thereafter Avoidance of smoking tobacco should be recommended for all patients Pulmonary function testing (PFT) and focused radiologic assessment for allogeneic recipients at 1 y for signs or symptoms of compromise, or earlier as clinically indicated. Annual testing for those with deficits or appropriate clinical circumstances. Some experts suggest screening PFT evaluation every 3-6 mo in the first 2 y, particularly in patients with cGVHD PFTs should be performed for autologous recipients with known pretransplant deficits or exposure to radiation or other lung toxic agents Radiographic evaluation as determined by diagnostic PFT testing or based on symptoms
	Endocrine	Hypothyroidism Hypoadrenalism Gonadal failure Growth	Radiotherapy to head, neck, mantle TBI Prolonged corticosteroid usage TBI Intensive chemotherapy Young age Intensive prior chemoradiotherapy CNS radiotherapy Hypothyroidism Gonadal insufficiency TBI Corticosteroids	Thyroid function testing yearly post transplant in all patients, or if relevant symptoms develop Slow terminal tapering of corticosteroids for those with prolonged exposure Consider stress doses of corticosteroids during acute illness for patents who had received chronic corticosteroids Annual clinical and endocrinologic gonadal assessment for postpubertal women Clinical and endocrinologic gonadal assessment for prepubertal women within 1 y of transplant, with further follow-up as determined by pediatric endocrinologist in the peripubertal period Gonadal function in men, including FSH, LH, and testosterone, should be assessed as warranted by symptoms (lack of libido, erectile dysfunction) Monitor growth velocity in children annually, assessment of thyroid, and growth hormone function if growth velocity is abnormal
	Ocular	Cataracts Keratoconjunctivitis sicca Microvascular retinopathy	TBI, corticosteroids GVHD, TBI Cyclosporine, radiotherapy	Routine clinical evaluation at 6 mo, 1 y, and yearly thereafter, with instruction regarding sicca and cataract risk Schirmer testing for those with cGVHD Some experts recommend routine ocular exam (visual acuity; fundus exam) at 1 y for all patients, subsequent frequency of screening individualized according to symptoms or predisposing factors Prompt ophthalmologic examination in all patients with visual symptoms
	Skeletal	Osteopenia Avascular necrosis	Corticosteroids TBI Inactivity Gonadal insufficiency Corticosteroids TBI Male gender	Dual photon densitometry at 1 y for adult women or any patient with prolonged corticosteroid or calcineurin inhibitor exposure. Subsequent densitometry testing determined by defects or to assess response to therapy Exercise, calcium and vitamin D supplementation, and bisphosphonates are treatment options for osteopenia and may help prevent loss of bone density. Clinicians should assess the role of gonadal and thyroid function in patients with decreased bone density Some experts recommend use of bisphosphonates as prophylaxis for patients at high risk due to chronic corticosteroid usage Screening for avascular necrosis is not recommended
	Second cancers	Solid tumors Hematologic malignancies Posttransplant lymphoproliferative disorders	Chemotherapy Radiotherapy Immunodeficiency Chronic GVHD EBV infection	Risk awareness counseling annually Screening clinical assessment annually Routine self-examination of breasts and skin, as per health care maintenance section Pap smear and mammogram annually as per health care maintenance section. Some experts recommend screening mammography earlier than age 40 for women with radiation exposure Avoidance of tobacco or excessive, unprotected UV exposure
	Nervous system	Leukoencephalopathy Late infections Calcineurin neurotoxicity Peripheral neuropathy	Cranial radiotherapy Intrathecal chemotherapy Fludarabine GVHD Chemotherapeutic exposure	Clinical evaluation for symptoms and signs of neurologic dysfunction at 1 y Diagnostic testing (radiographs, nerve conduction, etc.) for those with symptoms or signs
	Kidneys and bladder	Nephropathy Bladder dysfunction	TBI, platinum exposure Adenovirus, CMV Cyclophosphamide	Blood pressure assessment at every clinic visit, with aggressive hypertension management Screening assessment of blood pressure, urine protein, BUN, and creatinine at 6 mo, 1 y, and annually if abnormalities on earlier studies Ultrasonography and/or renal biopsy as warranted to diagnose etiology of renal insufficiency
	Vascular	Coronary disease Cerebrovascular disease	Gonadal failure	Routine clinical assessment of cardiovascular risk factors as per health maintenance Clinical assessment for vascular complications at regularly scheduled follow-up visits Testing for hypercoagulability for patients with significant thrombosis history
	Quality of life and psychosocial adjustment	Depression Anxiety Fatigue Sexuality	Prior psychiatric morbidity Gonadal failure	Clinical assessment throughout recovery period, at 6 mo, 1 y, and annually thereafter, with mental health professional counseling recommended for those with recognized deficits Encouragement of robust support networks Query adults about sexual function at 6 mo and yearly
	General health			Recommended screening as per general population (see text)

Table 2. EBMT-CIBMTR-ASBMT Abbreviated Summary Recommendations for Screening and Prevention in Long-Term HCT Survivors Organized by Time after Transplantation

	Recommended Screening/Prevention	6 mo	1 y	Annually
	Immunity
	Encapsulated organism prophylaxis	3	3	3
	PCP prophylaxis	1	3	3
	CMV testing	3	3
	Immunizations		1	1
	Oral complications
	Dental assessment	1	1	1
	Liver
	Liver function testing	1	1	+
	Serum ferritin testing		1	+
	Respiratory
	Clinical pulmonary assessment	1	1	1
	Smoking tobacco avoidance	1	1	1
	Pulmonary function testing		2	+
	Chest radiography	+	+	+
	Endocrine
	Thyroid function testing		1	+
	Growth velocity in children		1	1
	Gonadal function assessment (prepubertal men and women)	1	1	1
	Gonadal function assessment (postpubertal women)		1	1
	Ocular
	Ocular clinical symptom evaluation	1	1	1
	Schirmer testing		3	3
	Ocular fundus exam		1	+
	Skeletal
	Bone density testing (women and patients with prolonged corticosteroid or calcineurin use)		1	+
	Second cancers
	Second cancer vigilance counseling		1	1
	Breast/skin/testes self-exam		1	1
	Clinical screening for second cancers		1	1
	Pap smear/mammogram (over age 40)		1	1
	Nervous system
	Neurologic clinical evaluation		1	+
	Kidney
	Blood pressure screening	1	1	1
	Urine protein screening	1	1	+
	BUN/creatinine testing	1	1	1
	Vascular
	Cardiovascular risk factor assessment		1	1
	Psychosocial
	Psychosocial/QOL clinical assessment	1	1	1
	Sexual function assessment	1	1	1

1 = recommended for all transplant patients. 2 = recommended for allogeneic patients only. 3 = recommended for any patient with ongoing cGVHD or immunosuppression. + = reassessment recommended for abnormal testing in a previous time period or for new signs/symptoms.

A broad constellation of medical issues faced by late survivors of transplantation is presented. Most of the late complications discussed here pertain particularly to allogeneic recipients. However, autologous recipients are at risk for many of the late complications and may experience unusual toxicity or immune impairment following transplantation that places them at risk similar to allogeneic recipients. Therefore, although some of the following recommendations do not generally apply to autologous recipients, providers should remain alert to these complications in all patients.

Immunity 

Infectious complications are common early after HCT. Immune reconstitution occurs gradually over time (generally 12-18 months). Immune recovery is slower for allogeneic recipients, particularly those with HLA-mismatched transplants and T-cell depleted grafts, and in survivors with graft-versus-host disease (GVHD). Bacterial, fungal, and viral infections may occur months or years after transplantation in those with delayed reconstitution. Although infectious risk is highest in the first 1-2 years after transplantation, risk of infection may continue long-term for some recipients of allogeneic transplants. Patients who are immunocompromised should be educated regarding their immune status and warning symptoms of infection and should be advised to seek early medical attention for infectious signs or symptoms. T-helper lymphocyte (CD4+) counts and CD4/CD8 ratios are good markers of immune reconstitution. Some experts use absolute CD4 levels (>400/μL) or CD4/CD8 ratio assessments as surrogate markers of the completeness of immune reconstitution to guide duration of viral or other infection prophylaxis therapy. Some experts provide supplemental immune globulin for patients with severe infections and IgG levels less than 400 mg/dL (4 g/L) and maintain levels until infection has abated.

Other Infectious Complications 

Although Pneumocystis carinii (Pneumocystis jiroveci) pneumonia (PCP) generally occurs during the first 6 months after HCT, patients are at risk for as long as immunosuppressive therapy is given for chronic GVHD. Autologous HCT recipients are also at risk of PCP, particularly during the first 6 months; risk may be substantial if there has been prolonged corticosteroid exposure before transplantation or particularly intensive conditioning. Sinusitis is an occasional complication, especially after allogeneic HCT, and is more frequent in patients with low immunoglobulin levels. Sinus pathogens are rarely identified because invasive diagnostic procedures are not frequently performed. Calcineurin antagonists induce mucosal hypertrophy that may add to sinus problems.

Recommendations:

•Patients with chronic GVHD should have antibiotic prophylaxis targeting encapsulated organisms given for as long as immunosuppressive therapy is administered. Some experts recommend antifungal prophylaxis in patients receiving chronic or high-dose corticosteroids for cGVHD.

•Administration of prophylactic antibiotics for oral procedures should follow the American Heart Association guidelines [7] for endocarditis prophylaxis.

•Some experts recommend that surveillance with CMV antigen or PCR testing for allogeneic HCT patients should be continued for the duration of chronic immunosuppression or chronic GVHD. Similarly, some experts recommend prophylaxis for HSV in patients receiving chronic immunosuppression for cGVHD.

•All HCT recipients should receive PCP prophylaxis for 6 months or as long as immunosuppressive therapy is given for treatment/prevention of chronic GVHD.

•Immunization with inactivated vaccines should be initiated at 1 year for all patients according to either the CDC guidelines or EBMT guidelines [8, 9]. Physicians may consider delayed initiation of immunization in situations where patients have little ability to respond, such as active steroidusage.

Oral complications 

Radiation therapy given as part of the conditioning regimen or as disease treatment before transplantation causes reduced saliva production. This can be short-lived or persistent. Chronic GVHD can also reduce saliva production. Since saliva is a key host defense against bacteria involved in dental caries, such individuals are at high risk for dental caries. An assessment for saliva production should be performed at the onset of chronic GVHD and repeated during follow-up under the supervision of a dental professional at intervals appropriate to the individual situation. Fluoride treatments are often recommended. Artificial saliva supplements may improve mastication of food and optimize nutrition.

Oral involvement with GVHD is frequent and can be painful, interfere with oral intake, and be complicated by infections. Chronic GVHD is a risk factor for development of intraoral malignancies. Corticosteroid mouth rinses or paste may improve symptoms of chronic GVHD.

Recommendations:

Liver complications 

Identifying the etiology of liver dysfunction following transplantation can be difficult. Useful information includes time of onset, type and trend of liver test abnormalities, history of liver dysfunction before or during transplantation, and presence of GVHD at other sites.

Chronic GVHD of the liver usually manifests as cholestasis with increased bilirubin and alkaline phosphatase. A liver biopsy should be considered to confirm clinical findings when isolated liver dysfunction occurs without other manifestations of GVHD. Therapy is with immunosuppressants. Ursodiol may be effective in conjunction with treatment of GVHD.

Patients with hepatitis B generally show mild to moderate liver disease on long-term follow-up. Chronic hepatitis C is often asymptomatic with fluctuating transaminase levels, but progression to cirrhosis and/or malignancy may occur in as many as 25% of cases. Tapering immunosuppressive therapy quickly and monitoring of liver function tests and viral load are critical to allow early treatment. Patients with hepatitis C virus (HCV) infection longer than 8-10 years should undergo liver biopsy to determine the degree of chronic active hepatitis. The effectiveness of treatment with ribavirin and/or interferon to prevent cirrhosis is not known. Use of interferon after allogeneic HCT may be problematic because of potential exacerbation of GVHD. Patients with chronic hepatitis may benefit from periodic consultation with a hepatologist.

Most long-term survivors will have some degree of iron overload as determined by serum ferritin levels. However, since serum ferritin is an acute phase reactant, it is primarily useful for screening for iron overload, and many experts would recommend confirmation with a liver biopsy depending upon the magnitude of elevation and the clinical context. Magnetic resonance imaging is being investigated as a noninvasive means to assess liver iron content. The clinical consequences of iron overload in transplant recipients have not been extensively evaluated. Iron overload has been associated with opportunistic infections and, when present in the setting of chronic viral hepatitis, may increase the risk of cirrhosis. Patients with iron overload should be counseled to avoid iron supplements and alcohol. Iron overload documented by liver iron content greater than 7 mg/g dry weight should be treated with phlebotomy and/or chelation therapy. Chelation therapy may be associated with an increased risk of fungal infections and should be used with caution.

Recommendations:

Complications of muscles and fascia 

Corticosteroid-induced muscle weakness is a consequence of selective atrophy of type II fibers in proximal muscles. It involves the legs more severely than the arms and tends not to affect neck flexor muscles. Myalgias frequently accompany the weakness. Weakness may be improved by physical therapy and isometric exercise. A thorough physical therapy evaluation and an individually designed program of activities can be helpful for maintaining and increasing strength. Whenever possible, the corticosteroid dose should be minimized. Alternate-day dosing reduces the risk of myopathy. Myopathy may be slow to resolve following discontinuation of corticosteroids.

Chronic GVHD may rarely produce polymyositis. Symptoms include severe proximal muscle weakness, myalgias, and arthralgias. Laboratory evidence includes elevated total creatine phosphokinase (CPK) or aldolase and, sometimes, elevated antinuclear antibody or rheumatoid factor titers. Muscle biopsy reveals necrotic muscle fibers, interstitial inflammation, and IgG deposits on immune fluorescent staining. Fasciitis, a manifestation of chronic GVHD, and sclerodermatous GVHD limiting range of motion at major joints may also occur. Therapy usually includes immunosuppressants.

Recommendations:

Respiratory complications 

Pulmonary complications occur commonly in HCT recipients. Risk estimates are affected by the length of follow-up and the type of routine assessments performed. Risk is generally higher with allogeneic transplantation. Major risk factors include infections, the extent and type of chemotherapy exposure (preconditioning and conditioning), radiation exposure, and immune-mediated lung injury. Mortality from late pulmonary complications is substantial. The value of screening with pulmonary function tests (PFTs) is not well defined; however, it may be the most sensitive early indicator of bronchiolitis obliterans. Early diagnosis may improve outcome since many conditions are irreversible in the later stages.

Idiopathic pneumonia syndrome (IPS)/interstitial pneumonitis is common in the early posttransplant period and can lead to late respiratory impairment. Etiologies include bacterial and viral infections, toxicity from radiation or chemotherapy, and chronic GVHD. Immune compromise delays recovery from infection, allowing greater damage to the lung interstitium. Certain chemotherapeutic agents (BCNU, bleomycin, busulfan, methotrexate, and melphalan) cause lung toxicity or enhance the damaging effects of radiation. Fractionation of radiation and lung shielding decrease radiation toxicity. Prophylaxis strategies focus on decreasing the risk of fungal and atypical bacterial lung infections such as PCP. Early identification of the cause of infections with improved viral surveillance permits earlier treatment. Prompt recognition of GVHD and institution of therapy may prevent lung fibrosis.

Bronchiolitis obliterans syndrome (BOS) (obstructive lung disease) occurs in 2-14% of allogeneic transplant recipients. GVHD, infections, and aspiration in those with esophageal damage have been implicated in development of BOS, although etiologies are not well defined. BOS may develop in patients with no other signs of chronic GVHD, and there may be minimal radiographic changes. PFTs are the only effective screening measure. Bronchodilator therapy may provide symptomatic relief but rarely improves obstruction. Corticosteroids and other immunosuppressive therapy are effective in up to 50% of patients. Treatment of infections may help prevent BOS. In patients with active GVHD, immune suppression with corticosteroids, cyclosporine, and/or other agents is appropriate.

Recurrent sinopulmonary infections are common in transplant recipients, particularly those with long-lasting immune suppression for GVHD or those with chronic tobacco smoke exposure. Smoking cessation is recommended for all patients. Appropriate vaccination is recommended, and in patients with ongoing immune deficiency, monitoring immune globulin levels is warranted, with targeted replacement as recommended elsewhere in these guidelines.

Recommendations:

Endocrine complications 

Chemotherapy, radiation therapy, and HCT can all result in impairment of endocrine function. The most significant endocrine complications are associated with radiation exposure but are also related to some chemotherapeutic agents (busulfan), chronic GVHD, and prolonged corticosteroid exposure.

Subclinical, compensated hypothyroidism, with elevated TSH and normal serum free T4 levels, occurs in 7-15% of patients in the first year after transplantation. The reported incidence of frank hypothyroidism is variable depending upon risk factors in the population studied. Single-dose ablative TBI is associated with a 50% incidence of overt hypothyroidism, whereas fractionated TBI is associated with an incidence of about 15%. The incidence reported after busulfan and cyclophosphamide is 11%. Treatment given before transplantation likely also contributes to the risk of thyroid abnormalities. The median time to diagnosis of hypothyroidism is nearly 4 years. When the TSH is elevated with normal T4 levels, assessment should be repeated in 2 months, or therapy should be initiated at the discretion of the treating physician. Patients diagnosed with hypothyroidism should receive thyroid hormone replacement, with reassessment about 6 weeks after initiation of therapy. Further individual dose adjustment should be based on periodic thyroid assessment, most often recommended at 6-month intervals. Autoimmune thyroiditis is reported; hyperthyroidism may also occur following radiation. Radiation to the neck and total body irradiation are associated with dose-related increases in risk of thyroid malignancy, often with long latent periods.

Gonadal dysfunction is highly prevalent in HCT recipients, with rates as high as 92% for males and 99% for females. The degree of dysfunction is dependent on age, gender, pretransplant therapy, and conditioning regimen. Although the risk of gonadal failure is high in all individuals, women generally experience higher rates of failure than do men. Most men have normal testosterone levels after transplantation, although germ cell damage (infertility) is a near-universal finding in men exposed to high doses of radiation or chemotherapy. Most reports suggest that prepubertal boys experience normal puberty and demonstrate normal testosterone levels following HCT. Testing and consideration of hormone replacement therapy for men is recommended based on symptoms. Failure to progress through puberty in a timely fashion should prompt referral for a full endocrinology evaluation.

Women are at high risk of hypergonadotropic hypogonadism after HCT. Hypogonadism is nearly universal after irradiation or busulfan. Risk is lower with cyclophosphamide alone. In general, ovarian endocrine failure is irreversible in adult women, but younger women, particularly prepubescent girls, have a better opportunity for recovery of gonadal function. Fractionation of radiation reduces the risk compared with unfractionated radiation. Prepubertal girls should be monitored closely for onset of puberty and, if puberty is not experienced by age 12 to 13, be referred for full endocrinology evaluation and consideration of hormone supplementation. Adult women should be evaluated by a gynecologist and will likely require hormone replacement therapy to maintain libido, sexual function, and bone density. Libido is often decreased and only partially corrected by HRT in women. Vaginal GVHD may result in strictures and synechiae. Supplemental vaginal lubrication is of importance and should be addressed by the treating physician.

Infertility is almost inevitable in men and women after transplantation. Consideration should be given to sperm or embryo preservation. Inadequate evidence exists to support widespread use of ovarian cortical tissue strip banking as a means to restore ovarian hormonal function after HCT outside of research protocols.

Transplant recipients have a low incidence of primary adrenal failure after HCT. Chronic therapy with corticosteroids for GVHD will suppress the pituitary-adrenal axis, but function usually recovers gradually once exogenous corticosteroid exposure ends. Greater length and intensity of exposure is generally associated with longer persistence of adrenal suppression. Patients with prolonged exposure to corticosteroids after HCT should have adrenal axis testing when withdrawing corticosteroids, particularly if symptoms of adrenal insufficiency develop. Secondary hyperglycemia is a common consequence of corticosteroid usage.

Growth in children may be adversely affected by HCT, depending upon their pretransplant therapy and conditioning regimen. A large body of data suggests that radiation is associated with growth defects in children who receive HCT. Cranial radiation, in particular, increases the risk of diminished growth in children. Some reports suggest that chemotherapy alone may cause growth deficiencies. Growth is a complicated process and may be adversely impacted by many additional factors, including general illness, nutritional deficits, hormonal deficiencies, long-term corticosteroids, and GVHD. The risk of impaired growth is greatest in the youngest children. Children should be closely monitored for appropriate growth velocity after HCT. A pediatric endocrinologist should evaluate children who do not achieve adequate growth, and assessment of growth hormone levels should be considered. Growth hormone deficiency following TBI has been demonstrated in some studies, but not in others. Since growth failure is likely to be multifactorial, consideration must be given to causes other than inadequate growth hormone. The benefits of growth hormone supplementation are unclear, since no randomized trial is reported. However, in children with demonstrated deficiency, supplementation is commonly prescribed.

Recommendations:

Ocular complications 

There are 3 main ocular late effects after HCT. Anterior segment ocular complications of keratoconjunctivitis sicca syndrome and cataracts are well described. Ischemic microvascular retinopathy is a posterior segment complication that is being increasingly recognized.

Ocular sicca syndrome is usually part of a more general sicca syndrome with xerostomia, vaginitis, and dryness of the skin and is associated with chronic GVHD. Ocular manifestations include reduced tear flow, keratoconjunctivitis sicca, sterile conjunctivitis, corneal epithelial defects, and corneal ulceration. The incidence reaches 20% 15 years after HCT but is higher (nearly 40%) in patients with chronic GVHD. Treatment includes aggressive management of chronic GVHD and continual use of topical lubricants. Topical corticosteroids may improve symptoms but can cause sight-threatening complications when inappropriately used in herpes simplex virus or bacterial keratitis. Topical retinoic acid or cyclosporine may also be used. Lacrimal punctal occlusion may improve conjunctival wetting. In general, contact lens usage is discouraged in patients with keratoconjunctivitis sicca because of an increased risk of abrasion; however, some soft contact lenses may contribute to moisture maintenance. Such an approach should occur only with the close supervision of an ophthalmologist.

Cataract formation is one of the most frequent late complications of TBI. After single-dose TBI, almost all patients develop cataracts within 3 to 4 years, and some need surgical repair. Fractionation of TBI reduces the incidence of cataract and delays onset. In patients conditioned without TBI, the probability of cataract formation at 10 years is <10%. Other risk factors for cataract formation after HCT are older age and the use of corticosteroids. Cataracts are effectively treated surgically. Surgery is indicated if vision is impaired and the impairment is interfering with daily life.

Ischemic microvascular retinopathy presents with cotton-wool spots and optic-disc edema. Retinopathy is observed almost exclusively after allogeneic transplantation, particularly in patients conditioned with TBI and receiving cyclosporine for GVHD prophylaxis. In most cases, retinal lesions resolve with withdrawal or reduction of immunosuppressive therapy, even in cases where visual acuity is decreased. Other ocular complications in the posterior segment include hemorrhage, bilateral optic disk edema, and infectious retinitis (herpes viruses including CMV, toxoplasmosis, and fungi).

Recommendations:

Skeletal complications 

Osteopenia is a systemic condition characterized by reduced bone mass and increased susceptibility to bone fracture. Osteoporosis is a more severe reduction in bone mass with greater susceptibility to bone fracture. The incidence and course of bone density abnormalities following HCT have been studied in relatively few large series. One year after transplantation both men and women may experience significant loss of bone density. The cumulative dose and duration of corticosteroid therapy and the duration of cyclosporine or tacrolimus therapy are associated with loss of bone mass. Preventive measures include regular physical activity, supplemental calcium and vitamin D, and consideration of estrogen replacement in deficient women. Bisphosphonate therapy may reduce risk of fracture in patients with established osteoporosis, although there are few clinical data supporting its use as a preventive measure.

Dual photon densitometry is currently the best tool to assess the degree of osteopenia. Osteopenia and osteoporosis are differentiated by the degree of reduction in bone mass and can be quantified by T and Z scores by dual photon densitometry. Normal values for bone density have not been well established in children, although it is clear that the loss of bone density and increased risk of fracture is a significant issue in children after HCT. Treatment choices for patients with osteopenia or osteoporosis include calcium and vitamin D supplementation, judicious estrogen replacement in women, exercise, reduction of corticosteroids, and bisphosphonate therapy. Instruction regarding fall-prevention strategies is recommended.

The incidence of avascular necrosis after HCT (AVN) is between 4% and over 10%. Pain is usually the first sign; however, standard radiographic evaluation may not detect abnormalities until late in the disease course. Early diagnosis is facilitated by magnetic resonance imaging. While the hip is the most frequent location (over 80% of the cases; bilateral involvement in more than 60%), other joints can be affected, including the knees (10% of patients with AVN), wrists, and ankles. Symptomatic relief of pain and orthopedic measures to decrease pressure on the joint can prove helpful, but most adult patients with advanced damage require surgical correction. While the results of joint replacement by surgery are excellent in the majority of the cases, long-term follow-up of these prostheses is needed in young patients with a long life expectancy. Corticosteroids (both total dose and duration) are the strongest risk factor for development of AVN. The other important risk factor is TBI (with the highest risk for a 10-Gy single dose or >12 Gy fractionated).

Recommended screening:

Secondary malignancies 

Second malignancies after HCT are a devastating late complication. Patients receiving a allogeneic HCT have a 2- to 3-fold increased risk of developing solid tumors, compared with an age-, gender-, and region-adjusted population. Nearly all cancer types are described after allogeneic and autologous transplant, including oral cancers, as mentioned above. Risk factors include radiation therapy, length and severity of immunosuppression, and chronic GVHD. Risk increases with time after transplantation, particularly for radiation-related malignancies. Recent analyses suggest that the risk of radiation-related solid tumors continues to increase beyond 10 years posttransplantation. The risk of secondary leukemia or myelodysplasia (MDS) after autologous HCT is also higher than anticipated, with an overall incidence of about 4% at 7 years after transplantation, with a median (range) onset of 2.5 years (3 months to 7 years) post transplantation. Risk appears to be increased for patients receiving prior alkylator therapy, prolonged administration of conventional chemotherapy, and higher doses of pretransplant irradiation.

Posttransplant lymphoproliferative disorders (PTLD) are a rare complication of allogeneic HCT associated with donor-recipient HLA disparity, T-cell depletion, and GVHD. The overall incidence is 1% at 10 years after HCT. Although these usually occur early (within 6 months of transplantation), PTLD is reported as late as 8 years after HCT. The majority of PTLD are associated with Epstein-Barr virus infection. Quantitative PCR detection of EBV can help establish the diagnosis, and many patients respond to anti-CD20 monoclonal antibody therapy.

Exposure to radiation and the photosensitizing effects of many commonly used transplantation-related medications increase the risk of skin cancers among recipients. Patients should be encouraged to reduce UV skin exposure through the use of high-SPF sunscreens or skin coverage.

Recommendations:

Central and peripheral nervous system complications 

Neurological complications after HCT may affect the central and peripheral nervous systems and are an important cause of morbidity. Though described in all transplant recipients, reported complication rates appear to be lowest in autologous recipients and increased in allogeneic and especially recipients of transplants from donors other than HLA-identical siblings. Complications include late CNS infections in immunocompromised patients, cerebrovascular complications such as subdural hematoma or stroke, calcineurin-induced CNS neurotoxicity, leukoencephalopathy resulting from intrathecal chemotherapy or cranial irradiation, and peripheral neuropathies related to chemotherapy exposure or Guillain-Barré syndrome. Nearly 20% of patients complain of impaired memory, attention span, and verbal fluency. Pediatric patients may experience neurocognitive deficits or developmental delays following exposure to radiation or chemotherapy. Subtle but meaningful cognitive changes may be difficult to detect using formal testing techniques.

Recommendations:

Renal complications 

Little is known about late renal dysfunction after transplantation, and the true incidence of end-stage renal disease is not well defined. Renal dysfunction after HCT can be caused by nephrotoxins used to control disease before transplantation, during conditioning, and in the peritransplant period and may also be related to the underlying disease (eg, multiple myeloma), type of transplant, recipient age, and previous renal function. Potential nephrotoxins include chemotherapy or conditioning agents such as platinum compounds, carmustine, and ifosfamide; irradiation (including TBI), antifungal and antiviral agents (acyclovir, foscarnet, amphotericin B, and aminoglycoside antibiotics); and immunosuppressive therapy to prevent or treat GVHD (calcineurin inhibitors). Glomerulonephritis and nephrotic syndrome are reported post HCT. Radiation nephritis is frequent after TBI and can present more than 6 months after HCT with renal impairment and hypertension, with nephritic changes on urinalysis. Aggressive control of hypertension can substantially improve outcome.

Patients with substantial hemorrhagic cystitis in the early posttransplant period experience a greater risk of later bladder wall scarring and contraction.

Recommendations:

Vascular complications 

Vascular complications such as arterial cerebrovascular, cardiovascular, and peripheral vascular events, as well as venous thrombosis and pulmonary embolism, are reported at an unusually young age after HCT. However, since these complications are rare, it is not yet clear whether they are higher after HCT than in an age-matched general population. Screening should focus on regular assessment of established cardiovascular risk factors as outlined under preventive health and clinical assessment for unusual vascular complications.

Recommendations:

Psychosocial adjustment 

Depressive symptoms and psychological distress are frequently observed in HCT survivors. Fatigue, anger, insomnia, and problems with marital relationships may also be seen. Pediatric patients may experience altered behavior patterns, changes in social habits, and changes in academic/school behavior. At the transition from acute convalescence to long-term follow-up, psychological distress may increase rather than abate as the patient and his/her family must cope with changes in roles, employment situations, and financial difficulties. Sexual dysfunction occurs in a significant number of survivors and may be multifactorial in origin, from depression to gonadal hormonal deficiency.

Spouses and other caregivers may also exhibit high levels of depression and psychological distress. They often report loneliness and low levels of perceived social support. Children may suffer from separation from 1 or both parents and the consequences of stress and upheaval in the family.

At a minimum, screening for depression is recommended every 6-12 months after transplantation as per the general health maintenance section below. Specific tools for screening for psychosocial difficulties after HCT are also available and could be used with a similar frequency to depression screening (Appendix 1).

Recommendations:

General screening and preventive health