Adult Survivors Of Childhood Acute Lymphoblastic Leukemia Research Articles

Exercise and QUality Diet after Leukemia: A Randomized Weight Loss Trial among Adult Survivors of Childhood Leukemia in the Childhood Cancer Survivor Study.

Obesity is prevalent in childhood cancer survivors and interacts with cancer treatments to potentiate risk for cardiovascular (CV) death. We tested a remote weight-loss intervention trial that was effective among adults with CV risk factors in a cohort of adult survivors of childhood acute lymphoblastic leukemia (ALL) with overweight/obesity. In this phase III efficacy trial, survivors of ALL enrolled in the Childhood Cancer Survivor Study with a body mass index ≥25 kg/m2 were randomized to a remotely delivered weight-loss intervention versus self-directed weight loss, stratified by history of cranial radiotherapy. The primary endpoint was the difference in weight loss at 24 months in an intent-to-treat analysis. Analyses were performed using linear mixed-effects models. Among 358 survivors (59% female; median attained age: 37 years; IQR: 33-43 years), the baseline mean (SD) weight was 98.6 kg (24.0) for the intervention group (n = 181) and 94.9 kg (20.3) for controls (n = 177). Adherence to the intervention was poor; 15% of individuals in the intervention group completed 24/30 planned coaching calls. Weight at 24 months was available for 274 (77%) participants. After controlling for cranial radiotherapy, sex, race/ethnicity, and age, the mean (SE) change in weight from baseline to 24 months was -0.4 kg (0.8) for the intervention group and 0.2 kg (0.6) for control participants (P = 0.59). A remote weight-loss intervention that was successful among adults with CV conditions did not result in significant weight loss among adult survivors of childhood ALL. Future interventions in this population must be tailored to the unique needs of survivors to encourage engagement and adherence. See related In the Spotlight, p. 1147.

Neurocognitive outcome and associated factors in long-term, adult survivors of childhood acute lymphoblastic leukemia, treated without cranial radiation therapy.

There is limited research on neurocognitive outcome and associated risk factors in long-term, adult survivors of childhood acute lymphoblastic leukemia (ALL), without treatment of cranial radiation therapy. Moreover, the impact of fatigue severity and pain interference on neurocognition has received little attention. In this cross-sectional study, we examined neurocognitive outcome and associated factors in this population. Intellectual abilities, verbal learning/memory, processing speed, attention, and executive functions were compared to normative means/medians with one sample t tests or Wilcoxon signed-rank tests. Associations with risk factors, fatigue severity, and pain interference were analyzed with linear regressions. Long-term, adult survivors of childhood ALL (N = 53, 51% females, mean age = 24.4 years, SD = 4.4, mean = 14.7 years post-diagnosis, SD = 3.4) demonstrated above average intellectual abilities, but performed below average in attention, inhibition, processing speed, and shifting (p < 0.001). Executive functioning complaints were significantly higher than normative means, and positively associated with fatigue (p < 0.001). There was no interaction between sex and fatigue and no neurocognitive impairments were associated with pain interference, risk group, age at diagnosis, or sex. Long-term, adult survivors of ALL treated without cranial radiation therapy, demonstrate domain-specific performance-based neurocognitive impairments. However, continued research on the neurocognitive outcome in this population as they age will be important in the coming years. Executive functioning complaints were frequently in the clinical range, and often accompanied by fatigue. This suggests a need for cognitive rehabilitation programs.

Accelerometry-based assessment of physical activity and sedentary behavior in adult survivors of childhood acute lymphoblastic leukemia and their healthy peers

Adult survivors of childhood acute lymphoblastic leukemia (ASALL) compose a specific group that faces an increased risk of experiencing late effects of their earlier treatment. Physical activity (PA) may be one of the appropriate means for preventing or minimizing the late effects of treatment. The main purpose of this study is to characterize device-measured PA and sedentary behavior (SB) among ASALL. The specific objective was to compare the movement behavior with a group recruited from the healthy population and to determine the degree of compliance with health recommendations for PA in the adult population. Twenty ASALL and 21 healthy control group (CG) members participated in the study. Participants were between 18 and 30 years old. Movement behavior was assessed for seven days using an Axivity AX3 accelerometer and a 24-h wearing protocol. Movement behavior was characterized by the amount of time spent in SB, light PA (LPA), moderate PA (MPA), and vigorous PA (VPA). There were no significant differences in movement behavior or compliance with PA recommendations between the ASALL and CG. During the week, the ASALL accumulated 711 min per day of SB vs. 636 min per day in the CG (p = 0.26); the ASALL had 186 min per day of LPA vs. 201 min per day in the CG (p = 0.47); the ASALL had 132 min per day of MPA vs. 147 min per day in the CG (p = 0.25); and the ASALL had 5 min per day of VPA vs. 4 min per day in the CG (p = 0.48). All research participants (ASALL and CG) met the PA recommendations of > 150 min per week for moderate PA. The results of our study suggest that ASALL, even after suffering from that disease in childhood, display comparable levels of PA and SB to their healthy peers. Both groups met the health recommendations for PA. The device-based monitoring of PA and SB should be an integral part of monitoring the late effects of treatment.

Energy cost of walking in obese survivors of acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort.

Adult survivors of childhood acute lymphoblastic leukemia (ALL) have impaired adaptive physical function and poor health-related quality of life (HRQoL). Obesity may contribute to these impairments by increasing the physiological cost of walking. Due to treatment exposures during ALL therapy, survivors' cost of walking may be more impacted by obesity than the general population. Therefore, we examined associations between obesity, persistent motor neuropathy, and energy cost of walking; and examined associations between energy cost of walking, adaptive physical function, and HRQoL, in adult survivors of childhood ALL vs. community controls. Obesity was measured via body mass index (BMI) and body fat percentage. The physiological cost index (PCI) was calculated from the six-minute walk test. Adaptive physical functioning was measured using two tests: the timed up and go (TUG) test and the physical performance test. Persistent motor neuropathy was measured using the modified total neuropathy score; HRQoL was measured using the Short-Form-36 questionnaire. The associations between obesity and PCI were evaluated using multivariable linear regressions in adult survivors of childhood ALL (n = 1,166) and community controls (n = 491). Then, the associations between PCI, adaptive physical functioning and peripheral neuropathy were examined using multivariable linear regressions. Finally, to determine the association between obesity, and neuropathy on PCI, while accounting for potential lifestyle and treatment confounders, a three model, sequential linear regression was used. Obese individuals (BMI > 40 kg/m2 and excess body fat percentage [males: >25%; females: >33%]) had higher PCI compared to those with normal BMI and body fat percentage (0.56 ± 0.01 vs. 0.49 ± 0.009 beats/meter p < .01; and 0.51 ± 0.007 vs. 0.48 ± .0006 beats/meter p < .01, respectively). Treatment exposures did not attenuate this association. Increased PCI was associated with longer TUG time in survivors, but not community controls (6.14 ± 0.02 s vs. 5.19 ± 0.03 s, p < .01). Survivors with PCI impairment >95th percentile of community controls had lower HRQoL compared to un-impaired ALL survivors: 46.9 ± 0.56 vs. 50.4 ± 1.08, respectively (p < .01). Obesity was associated with increased PCI. Survivors with high PCI had disproportionately worse adaptive physical function and HRQoL compared to controls. Survivors with increased energy costs of walking may benefit from weight loss interventions.

Fertility Status Among Long-Term Childhood Acute Lymphoblastic Leukemia Survivors Enrolled between 1971 and 1998 in the EORTC Children Leukemia Group Trials 58741, 58831/2 and 58881

BackgroundThe survival of childhood acute lymphoblastic leukemia (ALL) has improved significantly over the last decades, with recently reported overall survival rates in Europe of up to 85% in children (<14 years) and 62% in adolescents (15-19 years) (Trama, Lancet Oncol 2016). The increased number of long-term survivors has made the management of side effects an increasingly important issue in pediatric oncology. In this context, the impact on fertility caused by widely employed ALL treatments such as alkylating agents, cranial radiotherapy, total body irradiation and orchiectomy has been an emerging concern over the last years. The aim of this study was to assess fertility among long-term childhood ALL survivors.MethodsBetween 2012 and 2017, a follow-up study was performed among childhood ALL (and acute lymphoblastic lymphoma) survivors enrolled between 1971 and 1998 in EORTC studies (58741, 58831/2, 58881) in France and Belgium. Patients <18 years (yrs) at diagnosis and ≥18 yrs at the time of the follow-up were eligible to fill out a questionnaire that included information about their fertility. The following fertility-related outcomes were evaluated: having menstrual cycles for females, intention to have children, having children, use of reproductive techniques to become pregnant and occurrence of negative pregnancy outcomes (miscarriage, medical abortion, birth defects), separately for males and females.ResultsOut of 1429 eligible patients, 502 (35%) filled out the questionnaire, 862 (60%) were lost to follow-up, and 65 (5%) refused to participate. Disease characteristics and relapse occurrence within one yr after diagnosis were comparable between these 3 groups.Among respondents (275 females, 227 males), approximately 14% were aged 10-17 yrs at diagnosis and almost 30% belonged to the NCI high risk group (Table 1). Approximately 12% received cranial radiotherapy and 6% of females and 8% of males underwent hematopoietic stem cell transplantation. Relapse occurred in 12% and 14% of females and males, respectively. The median time between the diagnosis and the socioeconomic evaluation was 20 yrs (range: 13-42). The median age at follow-up was 25 yrs (range: 18-53).All but 6 females had ever had menstrual cycles. At the time of the fertility evaluation, 93% out of females younger than 45 yrs of age (N=270) either had menstrual cycles, were pregnant, gave breast feeding or continuously used contraceptives. Among females who had tried to become pregnant, 89% had been pregnant, 75% had children and 12% used medical help to become pregnant. One fifth of the ever pregnant females had ever had a miscarriage. The incidences of other negative pregnancy outcomes (e.g. birth defect, medical abortion) were low.The average number of children females had was 0.36 (95% CI: 0.27-0.44). The expected number of children in a population with the same distribution of country, age, and yr of birth of the mothers based on national population registries was 0.55. However, as 52% of the females had a bachelor or master degree and only 3% had no secondary school diploma, this difference could possibly be explained by an overrepresentation of females with a high level of education in our sample.Among males who had tried to have children, 83% made their partner pregnant, 72% had children and 7% used medical help to make their partner pregnant. The incidence of negative pregnancy outcomes other than miscarriage was low.ConclusionsIn this first disease-specific European cohort study, we evaluated fertility among adult survivors of childhood ALL enrolled in EORTC trials, with a median time from the diagnosis of 20 yrs.Most survivors who tried to have children, succeeded (75% of females, 72% of males). However, the average number of children per female seemed to be lower than in the general population. The incidences of birth defects, and medical abortions were low, both among female survivors and the partners of the male survivors.Despite the large number of potentially eligible patients, we could evaluate only 35% of long-term survivors. We were unable to study the effect of specific treatment exposures due to the large variety of treatments that patients received, the association between some treatments (protocol dependent) and age at the fertility evaluation, and the need to stratify the analyses by sex. Improvements in the follow-up of childhood cancer survivors are needed for a better evaluation of the long-term outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Socioeconomic Outcomes Among Long-Term Childhood Acute Lymphoblastic Leukemia Survivors Enrolled between 1971 and 1998 in the EORTC Children Leukemia Group Trials 58741, 58831/2 and 58881

BackgroundOver the last 30 years, there has been a considerable progress in the survival of childhood acute lymphoblastic leukemia (ALL). With survival rates exceeding 85%, the long-term effects are of major interest. Exposure to treatments may have severe toxicities such as cognitive deterioration after cranial radiotherapy (CRT) and impaired general physical functioning after hematopoietic stem cell transplantation (HSCT). These late effects may negatively impact the socioeconomic functioning of survivors. The aim of this study was to assess the socioeconomic status of adult survivors of childhood ALL treated in EORTC trials and the effect of patient's and disease characteristics and treatment modalities.MethodsBetween 2012 and 2017, a cross-sectional follow-up study was performed among childhood ALL (and acute lymphoblastic lymphoma) survivors enrolled between 1971 and 1998 in EORTC trials (58741, 58831/2 and 58881) by centers from France and Belgium. Patients who were younger than 18 years at diagnosis and older than 18 years at the time of the follow-up were eligible. Those whose postal address could be retrieved were invited to fill out a questionnaire with information about their socioeconomic situation. Additionally, the treating institutions provided medical updates.The following socioeconomic outcomes were evaluated: being married or living with a partner, having a university degree, having a job, working part-time among those having a job and history of having a paid job.ResultsAmong 1429 eligible patients, 502 (35.1%) filled out the questionnaire, 862 (60.3%) were lost to follow-up and 65 (4.5%) refused to participate. The distribution of age and NCI risk group at diagnosis, initial central nervous system involvement and relapse within one year after diagnosis was comparable between respondents, those lost to follow-up and those who refused to participate.Out of 502 survivors participating in the study, 66 had experienced a relapse (13%), 33 (7%) received HSCT (26 after relapse) and 60 (12%) were treated with CRT (36 in first line treatment, Table 1). The median time between the diagnosis and the socioeconomic evaluation was 20 years (range: 13-42). The median age at follow-up was 25 years (range: 18-53). Among survivors at school at the time of the diagnosis, 22% retook one and 6% two or more years due to the disease and 4% were unable to finish their education. Interestingly, 21% of the survivors had more and only 10% had less educational ambitions due to the disease. More than a half of the survivors had at least a bachelor (undergraduate) degree, 64% had a job and 38% were married or lived with their partner. Among those 25 years of age or older, the percentages for obtaining a bachelor degree, having a job and having a partner were 54%, 84% and 57%, respectively.In a multivariate model including sex, age at diagnosis, country, age at follow-up, relapse, HCST and CRT both treatments were associated with a higher probability of not obtaining a bachelor degree (OR=3.25, 95% CI: 1.27-8.31 for HCST and OR=3.17, 95% CI: 1.35-7.44 for CRT) and HSCT was associated with not having a job (OR=3.55, 95% CI: 1.23-10.21, Table 2). We found no evidence of associations between treatment exposures and having a partner. The associations between age at diagnosis and risk group at diagnosis and the socioeconomic outcomes were not statistically significant. Having a relapse was associated with a higher probability of not having a partner (OR=1.99, 95% CI: 1.05-3.77) and working half-time (OR=2.40, 95% CI: 1.03-5.58), adjusting for sex, age at diagnosis, country and age at follow-up. These findings were consistent with those from a sensitivity analysis performed among survivors aged 25 years or older.ConclusionThis large study showed that, overall, long-term childhood ALL survivors enrolled in EORTC trials between 1971 and 1998 were characterized by a high level of socioeconomic participation. However, HSCT and CRT were associated with negative socioeconomic outcomes. Our study adds to the body of evidence supporting the omission of CRT when other treatment alternatives are sufficient, like in first line treatment. It also indicates the need to provide special support to the most vulnerable groups of childhood ALL survivors, in particular those who received HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Exercise and QUality diet After Leukemia (The EQUAL Study): An intervention trial in the Childhood Cancer Survivor Study (CCSS).

10015 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for obesity and cardiovascular (CV) disease. Exposure to cranial radiotherapy (CRT) increases risks. We tested whether a weight loss intervention that was successful in the general population could result in weight loss or improvements CV risk factors for ALL survivors. Methods: Obese and overweight 5-year ALL survivors diagnosed &lt; age 21 from CCSS were randomized to a 24-month remotely delivered diet/physical activity intervention or self-directed weight loss (control), stratified by CRT. The intervention emphasized a low calorie DASH diet and physical activity via an app, a website, and weekly coach calls. The primary endpoint was difference in weight loss after 24 months, using an intent-to-treat analysis. Secondary endpoints: differences in changes in blood pressure, cholesterol, and triglycerides. Analyses were performed using linear mixed effects; the study was designed to detect a difference of 2.75 kg. Results: Of 358 survivors (59% female, 91% White non-Hispanic, median age 37, IQR: 33-43), 181 were randomized to the intervention and 177 to control. Baseline mean (SD) weight was 98.6 kg (24.0) for intervention and 94.9 kg (20.3) for controls. 55 (30%) of intervention participants were adherent beyond one year. At 12 months, after controlling for CRT, sex, race/ethnicity, and age, the adjusted mean (SE) change in weight from baseline was -1.83kg (0.7) for intervention and -0.16kg (0.64) for control participants. At 24 months, the adjusted mean (SE) change in weight was -0.36kg (0.78) for intervention and +0.18kg (0.66) for control participants with the average difference of -0.54 kg (95%CI: -2.5,1.5, p=0.59) between the arms. A small proportion had at least 5% weight loss at 24 months (intervention 24%; control 17%). No significant differences in CV risk factors were observed. Conclusions: A 24-month phone and app/web-based diet and physical activity intervention that was successful for weight loss in the general population did not result in greater weight loss or improvement in CV risk factors among adult survivors of childhood ALL. Reduced adherence to the intervention beyond 12 months, or lack of ALL survivor-specific tailoring, may account for these findings. Clinical trial information: NCT02244411. [Table: see text]

Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.

Gut microbial composition difference between pediatric ALL survivors and siblings

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with high cure rates leading to rising numbers of long-term survivors. Adult survivors of childhood ALL are at increased risk of obesity, cardiovascular disease, and other chronic illnesses. We hypothesize that ALL therapy is associated with long-term gut microbiome alterations that contribute to predisposition to chronic medical conditions. We conducted a pilot study to test whether differences can be detected between stool microbiota of pediatric ALL survivors and their siblings. Stool samples were collected from 38 individuals under age 19 who were at least 1 year after completion of therapy for ALL. Stool samples collected from 16 healthy siblings served as controls. 16S ribosomal RNA gene sequencing was performed on the stool samples. Comparing microbiota of survivors to sibling controls, no statistically significant differences were found in alpha or beta diversity. However, among the top 10 operational taxonomic units (OTUs) from component 1 in sparse partial least squares discriminant analysis (sPLS-DA) with different relative abundance in survivors versus siblings, OTUs mapping to the genus Faecalibacterium were depleted in survivors. Differences in gut microbial composition were found between pediatric survivors of childhood ALL and their siblings. Specifically, the protective Faecalibacterium is depleted in survivors, which is reminiscent of gut microbiota alteration found in adult survivors of childhood ALL and reported in obesity, suggesting that microbiota alterations in pediatric ALL survivors start in childhood and may play a role in predisposition to chronic illness in later years of survivorship.

Cranial Irradiation in Childhood Acute Lymphoblastic Leukemia Is Related to Subclinical Left Ventricular Dysfunction and Reduced Large Artery Compliance in Cancer Survivors.

Long-term survivors of acute lymphoblastic leukemia (ALL), the most common childhood malignancy, are at remarkably increased risk of heart failure (HF) in middle age, most likely due anthracycline cardiotoxicity. The role of cranial radiation therapy (CRT) in the development of left ventricular (LV) dysfunction, a predecessor of overt HF, remains unclear. Our aim was to compare LV function and systemic arterial properties according to past CRT in young adult survivors of anthracycline-treated ALL. We studied young adult survivors of childhood ALL at a median of 16 years from diagnosis treated with anthracycline-based chemotherapy, with (n = 12) or without (n = 30) CRT. In addition to fractional shortening (FS) and ejection fraction (EF), LV function was quantified by tissue Doppler imaging of the mitral annulus. Aortic strain/distensibility and arterial compliance were derived from echocardiography and simultaneously recorded pulse pressure. Despite similar FS and EF, peak mitral annular systolic velocity (median (interquartile range): 9.0 (7.5–10.0) vs. 10.0 (8.8–11.5) cm/s, p = 0.05), and early diastolic velocity (13.8 (13.0–14.8) vs. 15.5 (14.0–17.3), p = 0.01) were decreased after chemotherapy combined with CRT compared to chemotherapy without CRT. Systemic arterial compliance was lower in post-CRT subjects (1.0 (0.8–1.2 vs. 1.4 (1.1–1.7) mL/mmHg, p = 0.002). Aortic strain and distensibility were similar regardless of prior CRT. In conclusion, lower arterial compliance and subclinical LV dysfunction may be possible late consequences of past CRT in adult survivors of childhood ALL. Whether arterial stiffening is associated with future HF development in CRT-exposed ALL survivors remains to be investigated.

Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study.

Greater than one-half of children who are treated for acute lymphoblastic leukemia (ALL) develop ≥1 treatment-related medical conditions in their lifetime, many of which are known risk factors for diabetes mellitus. In the current study, the authors evaluated the prevalence and risk factors of diabetes mellitus among clinically assessed adult survivors of childhood ALL METHODS: The authors performed a retrospective evaluation of data from survivors of ALL and community controls who were enrolled in the St. Jude Lifetime Cohort Study between October 1, 2007, and June 30, 2016. Participants were adults with ≥10years of survival of childhood ALL and community controls who completed clinical and laboratory evaluations. Data for the current analysis were abstracted from medical records. Exposures evaluated herein included chemotherapy and radiation exposures and medical history, including drug-induced diabetes mellitus. Of 1360 eligible adults who were ≥10-year survivors of childhood ALL, a total of 1044 completed the evaluations; these individuals had a mean age of 33.97±9.14years and 50.86% were male. The 368 controls, 45.65% of whom were male, had a mean age of 35.33±10.21years. Type 2 diabetes mellitus (T2DM) was found in approximately 7.47% of survivors and 3.80% of controls (odds ratio [OR], 2.07; 95% CI, 1.11-3.87). In adjusted models, among survivors, older age (OR, 1.05 for each additional year; 95% CI, 1.02-1.08), body mass index ≥30kg/m2 (OR, 7.40; 95% CI, 2.61-20.97), and drug-induced diabetes mellitus occurring during ALL therapy (OR, 4.67; 95% CI, 2.53-8.61) were found to be associated with T2DM. Adult survivors of childhood ALL are at an increased risk of T2DM. Adult survivors of childhood ALL who are of older age, with an overweight or obese body mass index, and/or who developed drug-induced diabetes mellitus during treatment should be closely monitored for T2DM during long-term follow-up.

Physical fitness and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime cohort.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for both treatment-related exercise intolerance and neurocognitive deficits. This analysis aimed to identify the association between exercise intolerance and neurocognitive impairments in ALL survivors. Cardiopulmonary exercise testing, results from a 2-hour standardized neuropsychological assessment, and self-report questionnaires were obtained for 341 adult survivors of childhood ALL and 288 controls. Multivariable modeling was used to test associations between oxygen uptake at 85% estimated heart rate (rpkVO2 ) and neuropsychological test and self-reported questionnaire domains, adjusted for sex, age at diagnosis, cranial radiation, anthracycline, and methotrexate exposure and tobacco smoking status. Compared with controls, survivors had worse rpkVO2 and performance on verbal intelligence, focused attention, verbal fluency, working memory, dominant/nondominant motor speed, visual-motor speed, memory span, and reading and math measures (all P<.001). In adjusted models, exercise intolerance was associated with decreases in performance of verbal ability, focused attention, verbal fluency, working memory, dominant motor speed, nondominant motor speed, visual-motor speed, memory span, reading academics, and math academics in survivors. This study demonstrates an association between exercise intolerance and neurocognitive outcomes. Research is needed to determine whether interventions that improve exercise tolerance impact neurocognitive function in ALL survivors.

Peripheral Neuropathy, Sensory Processing, and Balance in Survivors of Acute Lymphoblastic Leukemia.

Purpose To compare peripheral nervous system function and balance between adult survivors of childhood acute lymphoblastic leukemia (ALL) and matched controls and to determine associations between peripheral neuropathy (PN) and limitations in static balance, mobility, walking endurance, and quality of life (QoL) among survivors. Patients and Methods Three hundred sixty-five adult survivors of childhood ALL and 365 controls with no cancer history completed assessments of PN (modified Total Neuropathy Score [mTNS]), static balance (Sensory Organization Test [SOT]), mobility (Timed Up and Go), walking endurance (6-minute walk test), QoL (Medical Outcomes Study 36-Item Short Form Survey), and visual-motor processing speed (Wechsler Adult Intelligence Scale). Results PN, but not impairments, in performance on SOT was more common in survivors than controls (41.4% v 9.5%, respectively; P < .001). In multivariable models, higher mTNS scores were associated with longer time to complete the Timed Up and Go (β = 0.15; 95% CI, 0.06 to 0.23; P < .001), shorter distance walked in 6 minutes (β = -4.39; 95% CI, -8.63 to -0.14; P = .04), and reduced QoL (β = -1.33; 95% CI, -1.79 to -0.87; P < .001 for physical functioning; β = -1.16; 95% CI, -1.64 to -0.67; P < .001 for role physical; and β = -0.88; 95% CI, -1.34 to -0.42; P < .001 for general health). Processing speed (β = 1.69; 95% CI, 0.98 to 2.40; P < .001), but not mTNS score, was associated with anterior-posterior sway on the SOT. Conclusion PN in long-term ALL survivors is associated with movement, including mobility and walking endurance, but not with static standing balance. The association between processing speed and sway suggests that static balance impairment in ALL survivors may be influenced by problems with CNS function, including the processing of sensory information.

Obesity and Walking Efficiency in Survivors of Acute Lymphoblastic Leukemia

Treatment for childhood acute lymphoblastic leukemia (ALL) is associated with an increased risk of being overweight/obese, having neuromusculoskeletal impairment and mobility limitations. Obesity may contribute to mobility limitations by increasing the physiologic cost/effort associated with movement. PURPOSE: To evaluate associations between obesity and walking efficiency in adult survivors of childhood ALL. METHODS: ALL survivors (N=351, mean±SD age: 28.5±6.0 years, 51.6% male) and 342 age-, sex- and race-matched controls (N=342, 29.0±7.5 years, 51.2% male) were assessed for body mass index (BMI: kg/m2), body fat percentage (%BF) using dual x-ray absorptiometry, and completed the six minute walk test. Walking efficiency was characterized with the physiological cost index (PCI). PCI is calculated using the formula: (Maximal heart rate (HR) during walking – HR at rest)/distance walked; expressed as beats per meter (normal range 0.13-0.49 in adults). RESULTS: ALL survivors with BMI ≥40 kg/m2 had higher PCI values compared with normal weight survivors (0.63±.040 vs. 0.50±0.019, p<.01), adjusting for age, sex, physical activity, and cranial radiation exposure. ALL survivors with excess %BF (defined as > 25% for men and > 33% for women) also had higher PCI values compared to survivors with normal %BF (0.54±.013 vs. 0.47±0.017, p<.01). No associations between obesity and PCI were evident among controls. CONCLUSIONS: Obesity is associated with reduced walking efficiency in ALL survivors but not in healthy controls, suggesting that ALL survivors do not have the same capacity to compensate for excess body weight as their peers with no cancer history. Weight loss interventions may have a significant impact on daily activity in this population.

Young adult survivors of childhood acute lymphoblastic leukemia show evidence of chronic inflammation and cellular aging.

Large epidemiologic studies have reported the premature onset of age-related conditions, such as ischemic heart disease and diabetes mellitus, in childhood cancer survivors, decades earlier than in their peers. The authors investigated whether young adult survivors of childhood acute lymphoblastic leukemia (ALL) have a biologic phenotype of cellular ageing and chronic inflammation. Plasma inflammatory cytokines were measured using a cytometric bead array in 87 asymptomatic young adult survivors of childhood ALL (median age, 25 years; age range, 18-35 years) who attended annual follow-up clinic and compared with healthy, age-matched and sex-matched controls. Leukocyte telomere length (LTL) was measured using Southern blot analysis. Survivors had significant elevation of plasma interleukin-2 (IL-2), IL-10, IL-17a, and high-sensitivity C-reactive protein levels (all P < .05). A raised high-sensitivity C-reactive protein level (>0.8 mg/dL) was related to increased odds of having metabolic syndrome (odds ratio, 7.256; 95% confidence interval, 1.501-35.074). Survivors also had significantly shorter LTL compared with controls (median, 9866 vs 10,392 base pairs; P = .021). Compared with published data, LTL in survivors was similar to that in healthy individuals aged 20 years older. Survivors who received cranial irradiation had shorter LTL compared with those who had not (P = .013). Asymptomatic young adult survivors of childhood ALL demonstrate a biologic profile of chronic inflammation and telomere attrition, consistent with an early onset of cellular processes that drive accelerated aging. These processes may explain the premature development of age-related chronic conditions in childhood cancer survivors. Understanding their molecular basis may facilitate targeted interventions to disrupt the accelerated aging process and its long-term impact on overall health. Cancer 2017;123:4207-4214. © 2017 American Cancer Society.

Reduced microbial diversity in adult survivors of childhood acute lymphoblastic leukemia and microbial associations with increased immune activation

BackgroundAdult survivors of childhood cancers such as acute lymphoblastic leukemia (ALL) have health problems that persist or develop years after cessation of therapy. These late effects include chronic inflammation-related comorbidities such as obesity and type 2 diabetes, but the underlying cause is poorly understood.ResultsWe compared the anal microbiota composition of adult survivors of childhood ALL (N = 73) with healthy control subjects (N = 61). We identified an altered community with reduced microbial diversity in cancer survivors, who also exhibit signs of immune dysregulation including increased T cell activation and chronic inflammation. The bacterial community among cancer survivors was enriched for Actinobacteria (e.g. genus Corynebacterium) and depleted of Faecalibacterium, correlating with plasma concentrations of IL-6 and CRP and HLA-DR+CD4+ and HLA-DR+CD8+ T cells, which are established markers of inflammation and immune activation.ConclusionsWe demonstrated a relationship between microbial dysbiosis and immune dysregulation in adult ALL survivors. These observations suggest that interventions that could restore microbial diversity may ameliorate chronic inflammation and, consequently, development of late effects of childhood cancer survivors.

Obesity and Metabolic Syndrome Among Adult Survivors of Childhood Leukemia.

Treatment-related obesity and the metabolic syndrome in adult survivors of childhood acute lymphoblastic leukemia (ALL) are risk factors for cardiovascular disease. Both conditions often begin during therapy. Preventive measures, including dietary counseling and tailored exercise, should be initiated early in the course of survivorship, with referral to specialists to optimize success. However, among adults who develop obesity or the metabolic syndrome and who do not respond to lifestyle therapy, medical intervention may be indicated to manage underlying pathology, such as growth hormone deficiency, or to mitigate risk factors of cardiovascular disease. Because no specific clinical trials have been done in this population to treat metabolic syndrome or its components, clinicians who follow adult survivors of childhood ALL should use the existing American Heart Association/National Heart Lung and Blood Institute Scientific Statement to guide their approach.

Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for late cardiotoxic effects of cancer treatment, but conflicting evidence exists on the effects of anthracyclines on left ventricular (LV) diastolic function and exercise capacity. We performed a cross-sectional study with comprehensive echocardiography in 138 adult survivors of childhood ALL, median 23.4 years after diagnosis. Pulsed tissue Doppler measurements of early diastolic mitral annular velocities (e') were used for the assessment of diastolic function, and compared to 138 matched controls. Of the survivors, 133 also performed ergospirometry measuring peak oxygen uptake (VO2 max). Associations between cancer treatment, LV function, and VO2 max were analyzed. The survivor group had lower e' values than controls (e' septal 11.0 vs. 12.6 cm/s, P < 0.001), but the difference was confined to the subgroup of anthracycline treated survivors (median cumulative dose 120 mg/m(2) ). Anthracycline exposure was inversely correlated with e' (regression coefficient -1.581, P=0.009). Reduced VO2 max/kg occurred in 47% of the survivors, but more often in anthracycline treated survivors (56%) than anthracycline naïve survivors (17%, P<0.001). Anthracycline exposure was inversely correlated with VO2 max/kg (regression coefficient -3.084, P = 0.05 in multivariate analysis). Furthermore, associations were observed between measures of LV function and VO2 max/kg, and e' was the best predictor of VO2 max/kg (standardized coefficient 0.355, P < 0.001 in multivariate analysis). Adult survivors of childhood ALL have increased risk for impaired LV diastolic function and impaired exercise capacity, both associated with previous anthracycline exposure. Furthermore, there is an association between LV diastolic function and exercise capacity.

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

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.TableCNS Directed ThreapyNeurocognitive Deficit≥ 24 Gy< 24 GyHDMTXAttentionMild19.3%20.6%17.1%Severe31.6%22.8%14.1%Executive FunctionMild28.3%28.2%24.4%Severe35.4%24.1%20.3% DisclosuresNo relevant conflicts of interest to declare.

Neurocognitive Outcomes Decades After Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St Jude Lifetime Cohort Study

To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL). Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion. Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment. This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.