The metabolic cost of childhood ALL

In this issue of Blood, Oudin and colleagues report an increased prevalence of the metabolic syndrome (MS) in a cohort of adult survivors of childhood leukemia.¹  The coupling of a growing population of maturing childhood leukemia survivors with a syndrome that predisposes to cardiovascular disease, diabetes, and premature mortality is a call to arms for those clinicians who provide long-term care to survivors of childhood cancer.

Survival of acute lymphoblastic leukemia (ALL), the most prevalent childhood malignancy, now exceeds 80%. Consequently, there are more than 50 000 survivors of childhood ALL alive in the United States,²  and the ranks continue to swell. Although ALL survivors are generally at lower risk of developing long-term sequelae of therapy compared with survivors of other cancer diagnoses (notably Hodgkin lymphoma, brain tumors, and sarcomas), this group has a particular predisposition for metabolic derangements. Several studies have demonstrated an increased prevalence of MS and its components (central obesity, hypertension, impaired glucose metabolism, and dyslipidemia) in this population.^3,4  Patients treated with cranial radiation and hematopoietic stem cell transplantation (HSCT) appear to be particularly vulnerable: in the Oudin study, 18.6% of survivors treated with the combination of HSCT and total body irradiation met the criteria for MS. The true prevalence of MS in ALL survivors is unknown; published studies have either relied on patient self-report without confirmation of relevant laboratory results or have evaluated the prevalence in restricted cohorts of survivors, making their conclusions susceptible to bias.

Among the components of MS, obesity is a particular concern in ALL survivors. Patients treated with cranial radiation therapy are at increased risk for being overweight after therapy,^5,6  in part because of radiation-induced growth hormone insufficiency and leptin insensitivity. However, even survivors treated without radiation (who represent the majority of children with ALL treated in the current era) may be at risk for obesity as a consequence of their cancer therapy. Corticosteroids can cause increased energy intake during therapy, and may lead to physical inactivity secondary to myopathy, osteonecrosis, and reduced bone mineral density. Vincristine-induced peripheral neuropathy may further limit activity. In addition, unhealthy lifestyle behaviors such as poor diet and increased sedentary time may develop during treatment protocols that can last for 3 years or more.

While much work remains to be done to understand the pathophysiology of metabolic derangements in children treated for ALL, it is clear that these abnormalities place survivors at increased risk for cardiovascular disease and stroke. In fact, the Childhood Cancer Survivor Study has demonstrated that ALL survivors are 4.2 times more likely than the general population to die of cardiac disease,⁷  and 6.4 times as likely to suffer a late-occurring stroke.⁸  Consequently, all survivors of ALL, but particularly those exposed to cranial radiation therapy, HSCT, or total body irradiation, require regular follow-up care that is adapted to address the metabolic and cardiovascular risks that arise from their prior therapy. The Children's Oncology Group (and other international cooperative groups) has published guidelines for screening for MS in survivors (www.survivorshipguidelines.org). The challenge is to ensure that these guidelines reach their intended target.

A study of health care utilization in 8522 North American childhood cancer survivors revealed that less than 15% of survivors continue to receive follow-up care at a cancer center once they become adults.⁹  Most are seen by a primary care clinician in their community. Survivors' risks of developing late effects of therapy rise steadily over time without plateauing, in lock-step with a decreasing proportion seeking care at a cancer center.¹⁰  Primary care clinicians are often unaware of the specific risks faced by survivors and without this knowledge may not screen for MS in young survivors, particularly in the absence of obesity. Despite a higher prevalence of obesity in ALL survivors, many develop 1 or more cardiovascular risk factors without actually being obese. In the French cohort described by Oudin et al, only 14.5% had an elevated waist circumference, while 25.3% were hypertensive and 31.8% had low HDL cholesterol. Appropriate early screening will facilitate intervention with lifestyle counseling focused on increasing physical activity, improving diet, and curbing risky behaviors such as cigarette smoking. When necessary, hypertension, dyslipidemia, and impaired glucose tolerance can be treated pharmacologically, but intervention at this late stage is not enough. Pediatric oncologists must find ways to interrupt the path between leukemia treatment and the cascade of behavioral and pathophysiologic consequences that lead to MS. Treatment modifications such as the elimination of cranial radiation from most ALL regimens will modify the risk, and multidimensional programs targeting lifestyle during ALL therapy are being evaluated in ongoing clinical trials. As health care practitioners who care for children during and in the wake of cancer therapy, our mission is to ensure that the excellent cure rate of childhood ALL translates into lives unburdened by the cost of that cure.