Table 1.

Selected Screening Recommendations for Late Effects After HCT in Pediatric Patients

	Children’s Oncology Group (COG) Recommendations	Joint Transplant Society* Recommendations	UK Children’s Cancer and Leukaemia Group (CCLG) Practice Statement, BMT section**	Expert Panel Recommendations
				Screening	Management
Iron Overload	HCT section 95 AST, ALT, Bilirubin, Ferritin screening at entry into f/u and prn. Biopsy, chelation, phlebotomy as indicated	Serum ferritin at 1 year after HCT in patients who have received RBC transfusions; consider liver biopsy or imaging study for abnormal results based on magnitude of elevation and clinical context; subsequent monitoring is suggested for patients with elevated LFTs, continued RBC transfusions, or presence of HCV infection	History, examination Liver function tests yearly, ferritin as needed	Annual serum Ferritin; if elevated, consider T2* MRI	Phlebotomy or chelation
GI	HCT section 95 AST, ALT, Bilirubin, Ferritin screening at entry into f/u and prn Hepatology consultation for persistent abnormal LFTs Hep B,C viral testing as indicated	LFTs every 3–6 months in the first year, then individualized, but at least yearly thereafter Monitor viral load by PCR for patients with known hepatitis B or C, with liver and infectious disease specialist consultation Consider liver biopsy at 8– 10 years after HCT to assess cirrhosis in patients with chronic HCV infection	Only needed in presence of overt symptoms History, examination High index of suspicion for chronic GVHD in patients with cholestasis or acute hepatitis Microbiological, virological,biochemic al investigation of malabsorption if present	Annual screening for chronic GVHD Hepatitis virus infection screening Annual hepatocellular carcinoma screening for high risk patients: HCV or HBV infection Obesity, diabetes Low platelet count
Renal	Chemotherapy, alkylating agents section 13. Risks—therapy with ifosfamide, cisplatin, carboplatin, amino- glycosides, amphotericin, immunosuppressant s, XRT of kidney. Screen with lytes/BUN/Cr urinalysis at entry into f/u and prn. Rx electrolyte supplementation, nephrology for hypertension, proteinuria, progressive renal insufficiency.	Blood pressure assessment at every clinic visit, with aggressive hypertension management Assess renal function with BUN, creatinine and urine protein at 6 months, 1 year and at least yearly thereafter Consider further workup (kidney biopsy or renal ultrasound) for further workup of renal dysfunction as clinically indicated	Blood pressure, screen for hematuria/proteinuria (if protein positive, check urine protein: creatinine ratio), BUN/Cr yearly Consider GFR measurement if high creatinine High index of suspicion for chronic GVHD in patients with proteinuria/nephrotic syndrome	Monitor urine for albumin:creatinine ratio at day 80 and then annually. If ratio ≥ 30 and<300mg/gm, confirm with two + tests in 3–6 months and monitor every 3–6 months. If ratio >300mg/g, monitor every 3–6 months.	Treat with ACE inhibitor or ARB if albumin:creatinin e ratio is >300mg/gm on one occasion or if patient has persistent ratio above 30gm/kg on 3 occasions in a 6 month period and has hypertension
Pulmonary	HCT section 101 Risks—chest XRT/TBI, Bleomycin, Busulfan, BCNU, CCNU, cGVHD, Screen with CXR and PFTs at entry into f/u and prn. Avoid smoking, caution with SCUBA, anesthesia. Give influenza and pneumococal vaccines	Routine clinical evaluation at 6 months and 1 year after HCT and at least yearly thereafter Assessment of tobacco use and couselling against smoking PFTs and focused radiologic assessment for allogeneic HCT recipients	History, examination PFTs at 1 year (subsequent frequency depends on results and presence/absence of symptoms) Chest X-ray/consider high resolution CT if symptomatic or if severely abnormal PFTs High index of suspicion for chronic GVHD Advise against tobacco Advise influenza and pneumococcal immunizations	Pulmonary function testing for allogeneic recipients twice per year for two years with consideration for more frequent screening in recipients of mismatched or unrelated donors grafts, or patients with active chronic GVHD After two years, consider yearly f/u PFTs based upon symptoms and past measurements	If patients experience a decrease in PFTs >15% or a new pulmonary infiltrate, evaluate for infection/ GVHD. Refer to pulmonology for disease-specific care as needed.
Cardiac	XRT Section 71— multiple cardiac effects (CHF, cardiomyopathy, etc.) Risks higher with previous anthracyclines or combined with cyclo-phosphamide as conditioning for HCT. Screen with baseline echo/EKG, fasting glucose/lipid profile q2yrs. Recommendations regarding screening and treatment based upon condition and total anthracycline dose.	Routine clinical assessment of cardiovascular risk factors as per general health maintenance at 1 year and at least yearly thereafter Education and counseling on “heart “ healthy lifestyle (regular exercise, healthy weight, no smoking, dietary counseling) Early treatment of cardiovascular risk factors such as diabetes, hypertension, and dyslipidemia Administration of antibiotics for endocarditis prophylaxis according to American Heart Association guidelines	Echo – annually if abnormal, every 3–5 years if normal If heart included in radiotherapy field at any time (ie including TBI), consider review of other risk factors (eg measure fasting lipids) Advise against tobacco No other recommendations specific to HCT***	Annual CV risk assessment Blood Pressure each visit and at least annually; ECG/ECHO at least every 5 years, more frequently if anthracyclines, TBI or chest irradiation was given	Referral to cardiology for abnormal or declining cardiac function
Metabolic	XRT Section 49— Metabolic syndrome as a possible late effect of TBI. Screen with ht/wt/bp/BMI yearly plus fasting glucose/lipid profile every two years. Rx with diet, counseling, physical activity.	Screening for cardiovascular risk factors as outlined under “cardiac”	Measure fasting blood glucose, fasting lipids, HbA1c yearly Perform glucose tolerance test if fasting glucose elevated	Lipid profile & fasting glucose at least every 5 years; if abnormal, screen annually	No transplant- specific recommendation s available
Thyroid Dysfunction	XRT Section 64/65— hypo/hyperthyroidis m. Risks—XRT =10Gy, thyroid in field. Yearly screening, more frequently during rapid growth.	Thyroid function testing yearly post-HCT, or if relevant symptoms develop	TSH and FT4 yearly Palpate thyroid yearly Measure thyroid autoantibodies if TFTs abnormal Perform US scan and refer for fine needle biopsy if thyroid nodule palpated	TSH and FT4 annually: for 10 years after busulfan for at least 30 years after TBI PE of Thyroid yearly to screen for tumors after TBI	If TSH is high and FT4 normal, either treat or repeat in 2 months. Replace thyroid as indicated for low levels. Rare secondary thyroid tumors post-TBI are can be cured with surgery.
Growth Impairment	XRT Section 50— Growth Hormone Deficiency Risks—young age, TBI≥ 10Gy single fx, ≥12 Gy fractionated. Screen with dietary assessment, ht/wt/BMI every 6m until growth completed. Refer to endocrine for ht<3rd %, drop ≥ 2 % rankings, growth velocity<4–5cm/yr, lack of growth spurt.	Pediatric recipients: Monitor growth velocity in children annually; assessment of thyroid, and growth hormone function if clinically indicated	Measure height and weight, calculate height velocity 3–6 monthly until puberty and growth completed Measure IGF-1 and bone age in TBI recipients if concern about growth Refer to pediatric endocrinologist for consideration of dynamic GH testing in TBI recipients with slow growth (height velocity<25th centile)	Accurate measure of growth yearly through full growth (age 17 girls, 19 boys). Bone age as needed.	Bone age and referral to endocrine for patients not growing appropriately. GH therapy may unmask hypothyroidism.
Low Bone Mineral Density	HCT section 97 Risks—young age, caucasion, low BMI, steroids, calcineurins, cranial XRT/TBI, GH deficiency, delayed puberty, hyper- thyroidism, poor exercise, poor nutrition, smoking, alcohol use, carbonated beverages. Dexa at entry into long-term f/u and prn. Rx with Vit D, Ca, exercise. Endocrine consultation for osteoporosis/history of fractures.	Dual photon densitometry at 1 year for adult women, all allogeneic HCTrecipients and patients who are at high risk for bone loss; subsequent testing determined by defects or to assess response to therapy Physical activity, vitamin D, and calcium supplementation to prevent loss of bone density -Patients with cGVHD: Consider dual photon densitometry at an earlier date in patients with prolonged corticosteroid or calcineurin inhibitor exposure.	History, examination (fractures, back pain) Consider measurement of BMD by DEXA scan, especially in patients treated for GH deficiency or hypogonadism	Dexa-scan pre- HCT, 1 year post- HCT, yearly if Z- score<-1.	Patients with Z- score<−2, history of fractures refer to endocrine. Supplement Ca & Vit. D, weight- bearing exercise, avoid smoking, alcohol, caffeine
Osteonecrosis	HCT section 96 Risks—age ≥10 at HCT, steroids, TBI, focal XRT, allogeneic > autologous, cGVHD. Screen yearly with exam, MRI as clinically indicated.	MRI to evaluate patients with joint symptoms	History, examination Perform MRI if suspicion of ON Refer patients with ON to orthopedic surgeon	Consider MRI screening of asymptomatic patients on high- dose steroids. Early MRI screening of any patients with symptoms of joint pain, pain in groin or anterior thigh, limping.	Minimize steroids and alcohol consumption, offer analgesics, non-weight- bearing exercise, PT. Refer to Orthopedics.
Reproductive Risks	Chemotherapy, Alkylating agents section 7. Risks—combined doses of alylators/heavy metals/ DTIC/temazolamide with XRT to cranium or gonads. Screen FSH/LH/testosterone, Tanner staging ages 13–14 and as clinically indicated for delayed puberty, irregular menses. Semen analysis, repeat as indicated as resumption can occur 10 yrs after rx	Consider referral to appropriate specialists for patients who are contemplating a pregnancy or are having difficulty conceiving Counsel sexually active patients in the reproductive age group about birth control post-HCT	Assess pubertal stage 3–6 monthly until puberty and growth completed Measure sex hormones (testosterone or oestradiol), FSH, LH and inhibin B (if available) yearly from 10 years age Suggest semen analysis when appropriate At appropriate time: Discuss risk of impaired fertility, adverse pregnancy outcome and early menopause Discuss advisability of using contraception even with impaired fertility Discuss referral to Reproductive Medicine specialist for consideration of assisted reproduction technology when appropriate Refer patients with Leydig cell or ovarian failure to endocrinologist for hormone treatment	Women:monitor of ovarian failure (FSH, assess cycling) Men: semen analysis	Women: Anti- Mullerian Hormone (AMH) may assess ovarian reserve. Treat ovarian failure with hormone replacement therapy. Men: If oligospermia noted, could offer intracytoplasmic sperm injection.

^*Recommendations from the Center for International Blood and Marrow Transplant Research (CIBMTR), the American Society of Blood and Marrow Transplantation (ASBMT), European Group for Blood and Marrow Transplantation (EBMT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT), Bone Marrow Transplant Society of Australia and New Zealand (BMTSANZ), East Mediterranean Blood and Marrow Transplantation Group (EMBMT) and Sociedade Brasileira de Transplante de Medula Ossea (SBTMO)

^**Further information about higher risk factors and further actions is provided in each section.

^***Cross-references to Cardiac section of the Practice Statement