Late Outcomes of Adult Survivors of Childhood Acute Lymphoblastic Leukemia (ALL) Diagnosed Between 1963-2002: A Report from the St. Jude Lifetime (SJLIFE) Cohort Study
Authors: Mulrooney Daniel A. , Jones Kendra E. , Ness Kirsten K. , Crom Deborah B. , Ehrhardt Matthew J. , Brinkman Tara M. , Krull Kevin R. , Chemaitilly Wassim , Kun Larry E. , Kaste Sue C. , Armstrong Gregory T. , Srivastava Deokumar , Relling Mary V. , Pui Ching-Hon , Jeha Sima , Sandlund John T. , Green Daniel M. , Robison Leslie L. , Hudson Melissa M. 
Published: October 2019

Abstract
Introduction: Treatment for childhood ALL has evolved over the last five decades and transformed a once fatal disease to one with 5-year survival rates in excess of 90%. However, aging survivors of ALL are at risk for adverse health and social outcomes that significantly impact overall quality of life. Comprehensive clinical assessments of adults previously treated for childhood ALL are lacking, with most reports relying upon registry or self-reported data. To evaluate the impact of changes in therapy for ALL on the risk of late effects, we systematically screened and clinically assessed the largest cohort to date of adult survivors of childhood ALL treated over the last five decades. Our aim was to determine the occurrence of and risk factors for late chronic health conditions, neurocognitive deficits, and physical function limitations.
Methods: History/physical examination, laboratory analysis, neurocognitive testing, and physical fitness were assessed among 934 (65.7% of eligible) survivors of pediatric ALL ≥ 18 years of age, treated at St. Jude Children’s Research Hospital ≥ 10 years ago, and participating in the SJLIFE cohort study. Chronic health conditions were graded per CTCAE criteria (v4.03). Neurocognitive function was measured in the domains of attention and executive function using standard clinical tests. Using national norms, age-adjusted z-scores were calculated. Mild impairment was defined as a z-score between -1 to -2, severe as ≤ -2. Aerobic function was measured with the 6-minute walk test [6MWT] (abnormal ≤ 490 meters) and mobility by the timed up and go test [TUG] (abnormal > 6 seconds to rise from a chair, walk 3 meters, return, and sit). Log-binomial linear models were used to evaluate relative risk (RR) and 95% confidence intervals (CI) for associations between treatment and outcome.
Results: Survivors (50% female, 90% white) had a median age at diagnosis of 5.1 years (range 0.2-19.5), 31.2 years (18.4-59.7) at evaluation, and were 25.0 years (10.5-47.7) from diagnosis. Three hundred twenty-one (34.4%) received ≥ 24 Gy cranial radiation (CRT), 224 (24%) < 24 Gy, and 389 (41.6%) no CRT, of whom 373 were treated with high dose methotrexate (HDMTX). Nearly the entire cohort had at least one chronic condition (98%) and 59% a severe/life-threating condition (grades 3-4). The most common were obesity (70%), hypertension (70%), and peripheral sensory neuropathy (51.6%). Chronic conditions were more common in males (52% vs. 48%, p=0.003). By age 40, the cumulative prevalence of at least one chronic condition was 90% and 69% for a severe/life-threatening condition. After adjusting for age at diagnosis, age at evaluation, and gender, survivors exposed to CRT were more likely to have a severe/life-threatening condition (RR 1.3 95% CI 1.1-1.5) than those not exposed to CRT. One hundred sixty-eight survivors had 228 second neoplasms (121 malignant [79 non-melanoma skin cancers], 107 benign). Attention and executive function deficits (mild and severe) were identified across each category of CNS directed therapy (≥ 24 Gy CRT, < 24 Gy CRT, HDMTX) [table]. After adjustment for age at diagnosis and gender, those treated with CRT only were more likely to have mild (RR 1.4 95% CI 1.0-1.9) and severe (RR 2.2 95% CI 1.7-3.0) attention and executive function (RR 1.4 95% CI 1.1-1.8, RR 1.7 95% CI 1.4-2.2) deficits compared to those treated with HDMTX. Abnormal 6MWT was identified among 20.5% of the ALL survivors, 26.7% of those treated with CRT and 15.1% HDMTX. TUGS was abnormal in 35.5% of the cohort, 41.6% treated with CRT, 27.3% HDMTX. Adjusting for age at diagnosis, age at evaluation, gender, BMI, and educational attainment, CRT was significantly associated with impaired 6MWT (RR 1.8 95% CI 1.1-2.9) but not TUGS (RR 1.1 95% CI 0.9-1.4).
Conclusions: Systematic evaluation identified a substantial number of medical conditions, deficits in attention and executive function, and functional impairments in adult survivors of childhood ALL at a young age. Removal of CRT has significantly reduced, but not eliminated, the occurrence of late effects. Maintaining health and quality of life in this population requires significant medical surveillance, counseling, and lifestyle modifications.
Table CNS Directed Threapy Neurocognitive Deficit ≥ 24 Gy < 24 Gy HDMTX Attention Mild 19.3% 20.6% 17.1% Severe 31.6% 22.8% 14.1% Executive Function Mild 28.3% 28.2% 24.4% Severe 35.4% 24.1% 20.3%

Disclosures
No relevant conflicts of interest to declare.