Cardiovascular or metabolic
The three main LTFU categories of cardiovascular (CV) complications are heart failure (anthracycline but occasionally high‐dose cyclophosphamide‐related and augmented by radiation); radiation‐induced structural abnormalities in valves, coronary arteries or the conduction system; and development of metabolic syndrome (MS) components (dyslipidemia, hypertension, glucose intolerance). MS increase the risk for type 2 diabetes and atherosclerotic CV disease (CVD, myocardial infarction, vascular disease and stroke) [44–46].
Risk for CV toxicities is cumulative and includes genetics, pre‐HCT exposures plus side effects of cGVHD therapies (glucocorticoids, CNIs) since most patients take >2 years to discontinue all IST after an initial diagnosis of cGVHD; 10% require IST >5 years. Relative to siblings, allogeneic HCT survivors were 3–4 times more likely to report diabetes mellitus and twice as likely to report hypertension [47]. They were significantly more likely to develop hypertension than autologous recipients. TBI exposure was associated with an increased risk of diabetes mellitus (OR= 3.42, 95% CI: 1.55–7.52). Compared with a well‐matched general population, pediatric HCT survivors (>70% allogeneic recipients) had significantly higher rates of cardiomyopathy, stroke, dyslipidemia and diabetes [48], in an analysis that adjusted for sex, race, age, BMI, current smoking, daily fruit/vegetable intake, and recreational physical activity time. An analysis of potential risk reduction for serious CV outcomes (ischemic heart disease, cardiomyopathy, stroke) found that controlling dyslipidemia was most helpful, followed by control of hypertension, diabetes and smoking. Obesity was a risk factor for post‐HCT hypertension, dyslipidemia, and diabetes. Lower fruit/vegetable intake was associated with greater risk of dyslipidemia and diabetes, and lower physical activity level was associated with greater risk of hypertension and diabetes. Healthier survivor lifestyle characteristics attenuated the risk for all CV conditions assessed.
Pediatric survivorship recommendations usually begin by conducting an annual history and physical (dyspnea, chest pain, palpitations, exertional intolerance, edema), calculating anthracycline and radiation exposures, and requesting 2D‐echocardiography every 1–5 years depending on age plus exposures [12]. Variables used for COG’s risk algorithm require doxorubicin‐equivalent dose conversions, recognizing that total cumulative lifetime doses of anthracycline need to be multiplied by 4.0 (mitoxantrone), 5.0 (idarubicin), or by only 0.5 (daunorubicin) or 0.67 (epirubicin), due to potency differences. The Childhood Cancer Survivorship Study Cardiovascular Risk Calculator [49] uses information about exposures (anthracycline, alkylator, platinums, and radiation) but also demographics (gender, current age, age at HCT, use of medications to treat diabetes, dyslipidemia or hypertension) to predict incidence of heart failure, ischemic heart disease and stroke among survivors. Based on CCSG findings prevention of obesity and avoidance of smoking is important. Because improved survival and other benefits are observed in solid organ transplantation when dyslipidemia, hypertension and diabetes are addressed [13,50–53]. It is also reasonable to use medications to lower blood pressure and use statins to target lower LDL‐C after HCT when therapeutic lifestyle modifications are ineffective or not feasible. The lowest dose possible is used to minimize the potential for adverse drug interactions. Pleiotropic effects of statins may extend to improvement in renal function, hypertension, BMD, reduced incidence of AVN, and even improved control of GVHD [54–61].
Gastrointestinal or hepatic
HCT survivors have a >5‐fold burden of significant gastrointestinal (GI) complications compared to other cancer survivors which may include strictures of the esophagus and lower GI tract [62]. Strictures are most frequently due to cGVHD, prior candida esophagitis, GERD, or radiation >30 Gy; symptoms may include dysphagia and heartburn. Focal nodular hyperplasia is an often incidental benign finding, best diagnosed on gadolinium‐enhanced MRI and usually just needs to be monitored to avoid unnecessary invasive procedures [63,64]. Liver dysfunction due to GVHD, sequela of prior sinusoidal obstruction syndrome, hepatotropic viruses and iron overload may present with LFT abnormalities or hepatic synthetic defects. Chronic hepatitis B and C can lead to cirrhosis, portal hypertension and hepatocellular carcinoma. Unless GVHD is present at other sites, a liver biopsy might be indicated to confirm a liver GVHD diagnosis. Iron overload may exacerbate any LFT abnormality and so persistent elevation of serum ferritin might warrant checking transferrin saturation and possibly T2*MRI imaging to quantitate liver iron. Patients with significant LFT abnormalities should limit alcohol intake and avoid other hepatotoxins.
Renal or genitourinary
Chronic kidney disease (CKD), defined by structural damage or GFR <60 mL/min/1.73m2 for >3 months, is a common (18–42%) late effect in children and kidney damage can be associated with acute kidney injury (AKI), thrombotic microangiopathy (TMA), hemorrhagic cystitis, proteinuria, and hypertension [65–69]. Relevant exposures include chemotherapy (alkylators, fludarabine), radiation, CNIs, nephrotoxic antimicrobials, BK viremia or adenoviremia. There was a 4‐fold higher rate of CKD at 1 year among those with albuminuria and 6‐fold higher rate of non‐relapse mortality if overt proteinuria was present at day 100. Annual urinalysis for proteinuria (microalbuminuria), serum BUN, creatinine, electrolytes is standard, with reflexive nephrology consultation when abnormalities are found. Survivors should be screened for hypertension defined as average SBP and/or diastolic BP (DBP) that is ≥95th percentile for gender, age, and height on ≥3 occasions [67,68]. Major risk factors for idiopathic CKD are GVHD, acute renal failure, and after nonmyeloablative regimens, additional risk factors include long‐term use of calcineurin inhibitors and previous autologous HCT. Though hypertension after HCT has most commonly been treated with a long‐acting calcium channel blocker, blockade of the renin‐angiotensin axis using angiotensin‐converting enzyme inhibitors (ACEI) alone or in combination with angiotension II receptor blockers (ARB) may be a better choice in patients with idiopathic CKD. This concept is based upon studies using ACEI and ARBs in animal models of radiation‐induced injury, and upon recent clinical experience [70]. In addition to controlling blood pressure, ACEI and ARB might exert additional positive affects by reducing inflammation and inflammatory markers [71,72]. Extrapolating from studies in the diabetic population, in conjunction with the observation that albuminuria is frequent after HCT, raises the possibility that these agents might slow progression of CKD in patients with albuminuria after HCT. Controlled trials using ACEI or ARB after HCT are needed [70].
Muscle or connective tissue
Myopathy and/or myositis is a recognized late effect that is perhaps cGVHD‐related, but acute myopathy due to glucocorticoid therapy remains in the differential, as is debilitating, sometimes painful myositis that can be caused by statin therapy. Myopathy symptoms are often exacerbated by lack of physical activity and fatigue. Serum CPK, aldolase, CRP or ESR can be helpful in diagnosing GVHD‐associated myositis. A dynamically changing, informative marker for an individual patient, can sometimes be identified and followed serially for trends during the tapering of IST because a rise in that marker often heralds recurrent myositis symptoms.
Bone
The major LTFU complications are low bone mineral density (BMD) and avascular bone necrosis (AVN).
Key points of practice variation