Survivors Of Childhood Leukemia Research Articles

Reducing Learning and Psychosocial Disparities in Latino Children with Cancer: A Randomized Intervention Trial.

We developed a high-intensity parenting intervention (HIP) to help parents support the academic success of childhood cancer survivors (CCSs), who often face post-treatment challenges affecting their school-related functioning. This randomized controlled trial (NCT03178617) evaluated HIP's efficacy compared to lower-intensity, single-session, treatment-as-usual services (LIP) in Latino families. Primary outcomes were parenting efficacy and CCSs' school functioning; secondary outcomes included parenting knowledge and measures of CCSs' academic performance, attention, and functioning outside of school. 106 Latino survivors of childhood leukemia and lymphoblastic lymphoma (aged 6-12 years) and their parents were randomly assigned to HIP (n = 54) or LIP (n = 52). Linear mixed-effects models evaluated group differences across baseline, 6-month (T2), and 12-month (T3) assessments. Parenting efficacy and knowledge improved significantly in the HIP arm, resulting in higher scores vs LIP at T2 and T3 (P ≤ .01). No significant between-group differences were found in child school functioning; however, HIP children showed significantly better social functioning and performance on one measure of attention (CPT-3 commissions) at T3 (P < .05). While HIP adherence challenges were observed, with only 33 (61%) completing the intervention, exploratory analyses suggest that benefits were most evident among those who fully engaged. Satisfaction and perceived benefit were greater for HIP vs LIP at both time points (P < .05). Our results suggest the potential value of parent-directed behavioral interventions like HIP for CCSs and their families. Further studies are needed to address participation barriers and enhance engagement to maximize and sustain benefits.

Neurocognition in Survivors of Childhood Leukemia and Severe Sepsis

Neurocognition in Survivors of Childhood Leukemia and Severe Sepsis

Accelerated aging among survivors of childhood leukemia and lymphoma: Estimates of early onset and excess morbidity from the COMPASS model.

10028 Background: Cohort studies have detected an increased risk of accelerated aging among survivors of childhood cancer but the timing and magnitude are not known. Methods: To predict the clinical course of diseases of aging— cancer and cardiovascular disease — among survivors of childhood leukemia and lymphoma compared to the general population, we developed the Cancer Outcomes Microsimulation: Pediatric and Adolescent SurvivorShip (COMPASS) model. The model simulates 8 severe, disabling or life-threatening chronic health conditions (CHCs), including 4 subsequent cancers (breast, colorectal, glial tumors, sarcomas) and 4 cardiovascular diseases (heart failure, myocardial infarction/coronary artery disease, valvular disease, stroke), and excess mortality risks among survivors diagnosed between 1970 and 1999 over the course of their lifetimes. Treatment-related risks varied by patient characteristics (sex, age at diagnosis, diagnosis) and treatment exposures (chemotherapy, radiation dose) and were based on data from the Childhood Cancer Survivor Study (CCSS). Age-related risks and competing mortality were based on national databases (SEER, NHLBI, CDC Wonder). We used model calibration to identify parameter sets that generated outcomes consistent with observed data. Model outcomes included cumulative CHC risk. For comparisons to the general population, age-, sex, and diagnosis year-matched individuals who faced only age-related risks were simulated. Results: Among survivors representative of CCSS participants, the model estimated that 45% of leukemia and 65% of lymphoma survivors will develop at least 1 of the 8 CHCs by age 65. Compared to the estimated 20% cumulative risk for the general population, this represented a two- to three-fold excess morbidity risk among survivors. The age at which 20% of survivors developed at least 1 CHC was 51 years for leukemia and 42 years for lymphoma, suggesting an early onset of 14 and 21 years compared to the general population. Outcomes varied by diagnosis and treatment era due to competing risk changes. Among leukemia survivors diagnosed in the 1990s vs. 1970s, cumulative late recurrence mortality by age 40 (11% to 1%) declined. This combined with a reduction in radiation exposure (79% to 24%) resulted in a greater proportion living into adulthood and developing CHCs by age 65 (38% to 48%). In contrast, among lymphoma survivors, the proportion projected to develop a CHC by age 65 remained stable during the same period (62% to 65%) as late recurrence mortality risk declined (8% to 1%), but almost half still received radiation (90% to 49%). Conclusions: Despite improvements in therapy, leukemia and lymphoma survivors are projected to experience CHC early onset and excess morbidity, underscoring the importance of prevention-focused survivorship care and continued efforts to develop more targeted therapies.

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.

Late Adverse Effects after Treatment for Childhood Acute Leukemia.

The aim of this review is to raise awareness and knowledge among healthcare professionals and policymakers about late adverse effects in survivors of childhood leukemia. With contemporary treatment, over 90% of children with acute lymphoblastic leukemia (ALL) and over 60% with acute myeloid leukemia (AML) are cured. Large cohort studies demonstrate that 20% of ALL and most AML survivors have at least one chronic health condition by 20-25 years after diagnosis. These are life-changing or threatening in some survivors and contribute to increased premature mortality. We describe the frequency, causes, clinical features, and natural history of the most frequent and severe late adverse effects in childhood leukemia survivors, including subsequent malignant neoplasms, metabolic toxicity, gonadotoxicity and impaired fertility, endocrinopathy and growth disturbances, bone toxicity, central and peripheral neurotoxicity, cardiotoxicity, psychosocial late effects, accelerated ageing and late mortality. The wide range of late effects in survivors of haemopoietic stem cell transplant is highlighted. Recent developments informing the approach to long-term survivorship care are discussed, including electronic personalized patient-specific treatment summaries and care plans such as the Survivor Passport (SurPass), surveillance guidelines and models of care. The importance of ongoing vigilance is stressed given the increasing use of novel targeted drugs with limited experience of long-term outcomes. CONCLUSION: It is vital to raise awareness of the existence and severity of late effects of childhood leukemia therapy among parents, patients, health professionals, and policymakers. Structured long-term surveillance recommendations are necessary to standardize follow-up care.

Comparison of Adaptive Functioning Between Survivors of Childhood Acute Lymphoblastic Leukemia and Their Healthy Peers; An Experience from a Low- and Middle-Income Country

Introduction: Acute Lymphoblastic Leukemia (ALL) is the most common cancer diagnosed in children. Advances in treatment increased the survival rates of these children. One important long term aspect of survivorship is adaptive functioning, which plays a pivotal role in a child’s quality of life. This study compares the adaptive functions of childhood leukemia survivors with their healthy peers. Methods: This descriptive case control study was conducted at the Pediatrics Hematology/ Oncology Department of Indus Hospital and Health Network (IHHN), from November 2022 to April 2023. Survivor children and adolescents aged 12 to 18 years old treated for ALL were included. Cases were divided in two groups: Group A, ALL survivors, and Group B, healthy adolescents matched in age to the ALL survivors. VABS assessment was conducted by a qualified psychologist, to evaluate the adaptive functioning. All the information was entered and analyzed by SPSS version 20. Results: A total of 50 adolescent children were examined along with 50 healthy controls. 72% of the survivors had B-cell ALL (B-ALL), followed by 22% had T-cell ALL (T-ALL) and 6%, had Mixed Phenotype ALL. Mean of adaptive behavior composite score, communication skills, daily living skills and the socialization skills standard score were significantly lower among patients compared to controls (p=0.0001). Conclusion: Overall adaptive skills were significantly affected among the survivors. These findings underscore the importance of tailored interventions and support services to enhance the adaptive functioning and overall well-being of these resilient survivors.

Severe Sepsis During Treatment for Childhood Leukemia and Sequelae Among Adult Survivors

Children undergoing treatment for leukemia are at increased risk of severe sepsis, a dysregulated immune response to infection leading to acute organ dysfunction. As cancer survivors, they face a high burden of long-term adverse effects. The association between sepsis during anticancer therapy and long-term organ dysfunction in adult survivors of childhood cancer has not been examined. To determine whether severe sepsis during therapy for leukemia in childhood is associated with subsequent chronic health conditions in adult survivors. This cohort study included 644 adult survivors of childhood leukemia who were diagnosed between January 1, 1985, and July 19, 2010, and participated in the St Jude Lifetime Cohort Study. Participants were excluded if they received hematopoietic cell transplant or had relapsed leukemia. Data collection ended June 30, 2017. Data were analyzed from July 1, 2020, to January 5, 2024. Severe sepsis episodes, defined according to consensus criteria as septic shock, acute respiratory distress syndrome, or multiorgan dysfunction associated with infection occurring during anticancer therapy, were abstracted by medical record review for all participants. Common Terminology Criteria for Adverse Events-defined chronic health condition outcomes were independently abstracted. Associations between sepsis and cumulative incidence of chronic health conditions (eg, cardiovascular, pulmonary, kidney, neurological, and neurocognitive outcomes) were compared by adjusted hazard ratios from Cox proportional hazards logistic regression. Inverse propensity score weighting was used to adjust for potential confounders, including age, year of diagnosis, and leukemia type. The study sample consisted of 644 adult survivors of pediatric leukemia (329 women [51.1%] and 315 men [48.9%]; including 56 with a history of acute myeloid leukemia and 585 with a history of acute lymphoblastic leukemia) who were most recently evaluated at a median age of 24.7 (IQR, 21.2-28.3) years at a median time after leukemia diagnosis of 17.3 (IQR, 13.7-21.9) years. Severe sepsis during treatment of acute childhood leukemia occurred in 46 participants (7.1%). Participants who experienced severe sepsis during treatment were more likely to develop moderate to severe neurocognitive impairment (29 of 46 [63.0%] vs 310 of 598 [51.8%]; adjusted hazard ratio, 1.86 [95% CI, 1.61-2.16]; P < .001) significantly affecting attention, executive function, memory and visuospatial domains. Sepsis was not associated with long-term risk of cardiovascular, pulmonary, kidney, or neurological chronic health conditions. In this cohort study of long-term outcomes in survivors of pediatric leukemia, severe sepsis during anticancer therapy for leukemia was associated with a selectively increased risk for development of serious neurocognitive sequelae. Efforts to reduce the effects of anticancer therapy on long-term function and quality of life in survivors might include prevention of severe sepsis during therapy and early detection or amelioration of neurocognitive deficits in survivors of sepsis.

Neurocognitive and psychosocial outcomes in survivors of childhood leukemia with Down syndrome.

The primary aim of this study was to assess the feasibility of a developmentally tailored neurocognitive assessment in survivors of childhood acute leukemia with Down syndrome (DS-leukemia). A secondary aim was to compare outcomes in the DS-leukemia group to a historical comparison group of individuals with DS and no history of childhood cancer. Survivors of DS-leukemia (n = 43; 56% male, mean [SD] age at diagnosis = 4.3 [4.5] years; age at evaluation = 15 [7.9] years) completed a neurocognitive assessment battery that included direct measures of attention, executive function, and processing speed, and proxy ratings of attention problems and executive dysfunction. Direct assessment outcomes were compared to a historical comparison cohort of individuals with DS and no history of childhood cancer (DS-control; n = 117; 56% male, mean [SD] age at evaluation = 12.7 [3.4] years). Rates of valid task completion ranged from 54% to 95%, suggesting feasibility for most direct assessment measures. Compared to the DS-control group, the DS-leukemia group had significantly lower completion rates on measures of executive function (p = 0.008) and processing speed (p = 0.018) compared to the DS-control group. There were no other significant group differences in completion rates. Compared to the DS-control group, the DS-leukemia group had significantly more accurate performance on two measures of executive function (p = 0.032; p = 0.005). Compared to the DS-control group, the DS-leukemia group had significantly more problems with executive function as identified on proxy ratings (6.5% vs. 32.6%, p = <0.001). Children with Down syndrome (DS) are at increased risk for developing acute leukemia compared to the general population but are systematically excluded from neurocognitive outcome studies among leukemia survivors. This study demonstrated the feasibility of evaluating neurocognitive late effects in leukemia survivors with DS using novel measures appropriate for populations with intellectual developmental disorder.

Educational outcomes in siblings of childhood leukemia survivors: Factors associated with school difficulties and comparison with general population.

To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings and the general population. A cross-sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long-term follow-up program, was conducted, and education-related data were obtained via self-report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation. A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio [OR] 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long-term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population. Although the results are reassuring, socioeconomic and cancer-related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long-term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system.

Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.

An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors. We analyzed associations of neurocognitive deficits, as well as anxiety and depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors. Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5. Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications. Our results suggest that specific genes may be related to increased neuropsychological consequences.

Diastolic function assessment with left atrial strain in long-term survivors of childhood acute lymphoblastic leukemia

Abstract Background Survivors of childhood cancer might be at increased risk of diastolic dysfunction at follow-up due to cardiotoxic treatment exposure. Although diastolic function assessment is challenging in this relatively young population, left atrial strain might provide a novel insight into this evaluation. Purpose To examine diastolic function in a cohort of long-term survivors of childhood acute lymphoblastic leukemia survivors using left atrial strain and conventional echocardiographic parameters. Methods Long-term survivors who were diagnosed at a single center between 1985-2015 and a control group of healthy siblings were recruited. Conventional diastolic function parameters and strain were compared, the latter measured during the three atrial phases: reservoir (PALS), conduit (LACS) and contraction (PACS). Inverse probability of treatment weighting was used to account for differences between the groups. Results 90 survivors (24.6±9.7 years, time since diagnosis 18 [11-26] years) and 58 controls were analyzed. PALS and LACS were significantly reduced compared to the control group: 46.4±11.2 vs 52.1±11.7 (p=0.003) and 32.5±8.8 vs 38.2±9.3 (p=0.003), respectively (figure 1B). Conventional diastolic parameters and PACS were similar between the groups (figure 1A). The reductions in PALS and LACS were associated to cardiotoxic treatment exposure in age and sex adjusted analysis (≥ moderate risk, low risk, controls): 45.4±10.5, 49.5±12.9, 52.1±11.7 (padj=0.003) and 31.7±9.0, 35.2±7.5, 38.2±9.3 (padj=0.001), respectively (figure 2). Conclusions Long-term childhood leukemia survivors showed a subtle impairment in diastolic function that was detected using atrial strain but not with conventional measurements. This impairment was more pronounced in those with higher cardiotoxic treatment exposure.Figure 1Figure 2

Chronic Graft-Versus-Host Disease in Long-Term Survivors of Childhood Leukemia

Introduction: Hematopoietic stem cell transplantation (HSCT) remains a key treatment of high-risk childhood leukemia despite a wide range of long-term complications. Chronic graft-versus-host disease (cGvHD) is a severe complication of HSCT characterized by the immune response of transplanted cells against the recipient's organs. Adults undergoing HSCT are particularly susceptible to experiencing cGvHD. This complication is generally considered to be much less common when HSCT is performed during childhood and adolescence, though very limited long-term data is available. The present study from the LEA program aims to provide a better understanding of cGvHD and its long-term impact in long-term childhood leukemia survivors. Methods: LEA is a long-term follow-up program involving all childhood acute leukemia survivors treated in the French participating centers since 1980 (clinicaltrials.gov identifier: NCT01756599). The patients eligible to the present study were all patients included in the LEA cohort treated with HSCT. The primary objective of this cross-sectional study was to provide a long-term and comprehensive cGvHD evaluation in childhood leukemia survivors. Secondary objectives included identifying risk factors for cGvHD, assessing the impact of the disease on quality of life (QoL), and evaluating its evolution over time. The long-term cGvHD data were generated during an in-person dedicated follow-up visit by a clinician using 1) a dedicated questionnaire, and 2) the eGVHD application (UZ Leuven, Belgium) for standardizing the evaluation. QoL was evaluated using the SF36 questionnaire. Results: The study included a cohort of 446 patients treated for acute lymphoblastic leukemia (59%), acute myeloid leukemia (34%), or another hematological malignancy (7%). The age at HSCT was 8.9 ±0.3 years (mean ±standard error of mean). The dedicated long-term evaluation of cGvHD was performed 8.8 ±0.3 years after HSCT. The stem cell source was matched sibling donor (32%), mismatched related donor (9%), unrelated donor (37%), and cord blood (22%). HSCT was performed in first complete remission in 47% of patients. Myeloablative conditioning and total body irradiation were administered to 91% and 56% of patients, respectively. Anti-thymocyte globulin and ciclosporin were given to 49% and 94% of patients, respectively. At the time of the study, most patients never experienced (n=324, 73%) or recovered (n=28, 6%) from cGvHD. However, a significant proportion of patients (n=94, 21%) suffered long-term cGvHD of variable severity (45% mild, 33% moderate, and 22% severe) (Figure 1). Patients mostly had isolated organ defects (most frequently skin, eyes, and mouth defects). Multiple organs defects were also reported in some patients without recurrent patterns. At the time of cGvHD evaluation, patients suffering cGvHD mostly remained untreated (83%, n=78). Systemic treatment (ruxolitinib, ciclosporine, ibrutinib, and sirolimus), as well as local treatment were used in 11% and 5% of patients, respectively. cGvHD was significantly associated with several other long-term complications (thyroid function defects, cataract, lung function defects, osteonecrosis, diabetes). In a multivariate analysis (Table 1), age at HSCT was significantly associated with long-term cGvHD (odds ratio 1.06 for each additional year, 95% confidence interval 1.01-1.1, p=0.01). Sex, type of leukemia, time from HSCT, stem cell source, relapse, number of HSCT and total body irradiation were not significantly associated with long-term cGvHD risk. Long-term cGvHD had a marked detrimental effect on QoL, even after adjusting to the total number of other long-term complications. The physical and psychic SF36 adjusted composite scores in patients with versus without cGvHD were 50 ±1.5 versus 55 ±0.7 (p=0.01) and 38 ±1.9 versus 43 ±1.0 (p=0.01), respectively. Conclusion: This study shows that cGvHD is a frequent and severe complication in long-term survivors of childhood leukemia treated with HSCT. Higher age at HSCT is the main risk factor for long-term cGVHD in this population. Long-term cGvHD significantly and independently jeopardizes the survivors' QoL. This complication is probably underrecognized and undertreated. There is a great need for a systematic and standardized cGvHD evaluation in this population.

Right Ventricular Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: From the CTOXALL Study

There are limited data regarding right ventricle (RV) impairment in long-term survivors of childhood acute lymphoblastic leukemia (CLS). The aim of this study was to assess RV function in these patients using echocardiographic conventional measurements and automated RV strain. Echocardiographic recordings of 90 CLS and 58 healthy siblings from the CTOXALL cohort were analyzed. For group comparisons, inverse probability weighting was used to reduce confounding. The CLS group (24.6 ± 9.7 years, 37.8% women) underwent an echocardiographic evaluation 18 (11–26) years after the diagnosis. RV systolic dysfunction was found in 16.7% of CLS individuals using RV free-wall strain (RVFWS) compared to 2.2 to 4.4% with conventional measurements. RV systolic function measurements were lower in the CLS than in the control group: TAPSE (23.3 ± 4.0 vs. 25.2 ± 3.4, p = 0.004) and RVFWS (24.9 ± 4.6 vs. 26.8 ± 4.7, p = 0.032). Modifiable cardiovascular risk factors such as obesity (p = 0.022) and smoking (p = 0.028) were independently associated with reduced RVFWS. In conclusion, RV systolic function impairment was frequent in long-term survivors of childhood leukemia, underscoring the importance of RV assessment, including RVFWS, in the cardiac surveillance of these patients.

Evaluación de la función diastólica mediante strain de la aurícula izquierda en largos supervivientes de leucemia linfoblástica aguda infantil

Introduction and objectivesSurvivors of childhood cancer might be at increased risk of diastolic dysfunction at follow-up due to exposure to cardiotoxic treatment. Although assessment of diastolic function is challenging in this relatively young population, left atrial strain might provide a novel insight in this evaluation. Our aim was to examine diastolic function in a cohort of long-term survivors of childhood acute lymphoblastic leukemia by using left atrial strain and conventional echocardiographic parameters. MethodsLong-term survivors who were diagnosed at a single center between 1985 and 2015 and a control group of healthy siblings were recruited. Conventional diastolic function parameters and atrial strain were compared, and the latter was measured during the 3 atrial phases: reservoir (PALS), conduit (LACS) and contraction (PACS). Inverse probability of treatment weighting was used to account for differences between the groups. ResultsWe analyzed 90 survivors (age, 24.6±9.7 years, time since diagnosis 18 [11-26] years) and 58 controls. PALS and LACS were significantly reduced compared with the control group: 46.4±11.2 vs 52.1±11.7; P=.003 and 32.5±8.8 vs 38.2±9.3; P=.003, respectively. Conventional diastolic parameters and PACS were similar between the groups. The reductions in PALS and LACS were associated with exposure to cardiotoxic treatment in age- and sex-adjusted analysis (≥ moderate risk, low risk, controls): 45.4±10.5, 49.5±12.9, 52.1±11.7; Padj=.003, and 31.7±9.0, 35.2±7.5, 38.2±9.3; Padj=.001, respectively. ConclusionsLong-term childhood leukemia survivors showed a subtle impairment of diastolic function that was detected with atrial strain but not with conventional measurements. This impairment was more pronounced in those with higher exposure to cardiotoxic treatment.

Diastolic function assessment with left atrial strain in long-term survivors of childhood acute lymphoblastic leukemia

Background and objectivesSurvivors of childhood cancer might be at increased risk of diastolic dysfunction at follow-up due to exposure to cardiotoxic treatment. Although assessment of diastolic function is challenging in this relatively young population, left atrial strain might provide a novel insight in this evaluation. Our aim was to examine diastolic function in a cohort of long-term survivors of childhood acute lymphoblastic leukemia by using left atrial strain and conventional echocardiographic parameters. MethodsLong-term survivors who were diagnosed at a single center between 1985 and 2015 and a control group of healthy siblings were recruited. Conventional diastolic function parameters and atrial strain were compared, and the latter was measured during the 3 atrial phases: reservoir (PALS), conduit (LACS) and contraction (PACS). Inverse probability of treatment weighting was used to account for differences between the groups. ResultsWe analyzed 90 survivors (age, 24.6±9.7 years, time since diagnosis 18 [11-26] years) and 58 controls. PALS and LACS were significantly reduced compared with the control group: 46.4±11.2 vs 52.1±11.7; P=.003 and 32.5±8.8 vs 38.2±9.3; P=.003, respectively. Conventional diastolic parameters and PACS were similar between the groups. The reductions in PALS and LACS were associated with exposure to cardiotoxic treatment in age- and sex-adjusted analysis (≥ moderate risk, low risk, controls): 45.4±10.5, 49.5±12.9, 52.1±11.7; Padj=.003, and 31.7±9.0, 35.2±7.5, 38.2±9.3; Padj=.001, respectively. ConclusionsLong-term childhood leukemia survivors showed a subtle impairment of diastolic function that was detected with atrial strain but not with conventional measurements. This impairment was more pronounced in those with higher exposure to cardiotoxic treatment.

Impact of childhood leukemia on siblings: their long-term perception of family functioning and its relationship with their psychosocial characteristics using structural equation modeling.

In the context of pediatric cancer, siblings' adaptation and needs have been previously investigated; however, research on the long-term consequences on siblings, especially on their family environment, is scarce. We aimed to (1) assess the family functioning (FF) perceived by siblings of childhood leukemia survivors long after diagnosis and (2) explore characteristics likely associated and investigate associations with psycho-behavioral and social factors. Childhood leukemia survivors' siblings older than 11years were recruited through the LEA cohort, a French long-term follow-up program, and completed the family assessment device (FAD). Logistic regression analysis was used to determine factors likely associated with unhealthy functioning in families as perceived by siblings. Structural equation modeling (SEM) was used to examine relationships that predict siblings' perception of FF. We included 605 siblings (mean follow-up time from diagnosis 14.1 ± 6.8years), of whom 175 (28.9%) perceived unhealthy functioning. SEM showed that older siblings were more likely to perceive problematic functioning (β = 0.095, p = 0.014). Sex and leukemia burden had indirect effects on FF through mediators. Family financial situation at diagnosis was not associated with the risk of reporting unhealthy functioning. Our study contributed to identifying siblings at risk of facing family issues and reinforced the need to provide more consideration and suitable resources to avoid late consequences. Often considered as the "forgotten children", future research should focus on developing targeted interventions to facilitate family communication and improve siblings' social support. Overall, results regarding FF perceived by siblings are reassuring and provide new enlightening elements that allow for better support to all families.

Symptomatic osteonecrosis in French survivors of childhood and adolescent leukemia: a clinical and MRI study of LEA cohort

Osteonecrosis (ON) is a known complication of acute leukemia (AL) management, affecting 1%–10% of young patients and resulting in long-term morbidity. Widespread access to MRI over the past decade has allowed earlier detection and more accurate assessment. This study investigated clinical and MRI features of the 129 (2.5%) patients with symptomatic ON retrospectively recruited from the French LEA (Leucémies de l’Enfant et de l’Adolescent, or child and adolescent leukemias) cohort (n = 4,973). We analyzed data concerning ON risk factors, multifocal involvement, severe lesions detected by MRI, and patient quality of life (QoL). ON patients tended to be >10 years old at the time of AL diagnosis (odds ratio [OR]: 22.46; p < 10−6), female (OR: 1.8; p = 0.002), or treated for relapse (OR: 1.81; p = 0.041). They more frequently suffered from other sequelae (p < 10−6). Most necroses involved weight-bearing joints, and they were multifocal in 69% of cases. Double-blinded review of MRIs for 39 patients identified severe lesions in 14, usually in the hips. QoL of adolescents and adults was poor and permanently impacted after onset of ON. In conclusion, age >10 at time of AL diagnosis, female sex, and relapse occurrence were risk factors for multifocal ON; MRI revealed severe ON in a third of the patients considered; and ON was associated with persistently poor QoL affecting multiple domains. Future studies should include prospective data addressing ON management and seek to identify genetic markers for targeted screening enabling early ON detection and treatment.

A Clinical and Sociodemographic Risk Prediction Model Evaluating Adherence to Long-Term Care in Survivors of Childhood Leukemia

Background: Regular long-term follow-up care is important for surveillance and timely treatment of late effects after childhood leukemia therapy; however, structural barriers may disproportionately affect at-risk populations. Our objective was to evaluate factors associated with failure to utilize Long-Term Survivor (LTS) services following childhood leukemia treatment. Methods: We electronically extracted and manually curated electronic health records to identify childhood leukemia cases diagnosed between 2011 and 2014 at Texas Children's Cancer and Hematology Center. Individuals treated with a stem cell transplant, or those that transferred to an outside hospital, relapsed, or died within two years of end of treatment (EOT) were excluded. Address at the EOT was geocoded using ArcGIS to estimate travel time to the clinic and Area Deprivation Index, a composite measure of 17 neighborhood-level social determinants of health (SDOH). Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between clinical factors and attending LTS Clinic. LTS Clinic attendance was defined as at least one visit with an LTS provider at any time following EOT. Predictive performance of the model was evaluated using area under the receiver operating characteristic curve (AUC-ROC). Results: We identified 249 survivors of childhood leukemia that were eligible for LTS care in the designated time frame. Most were male (55%), non-Latino white (27%), Latino (57%), or non-Latino Black (10%) and were diagnosed at a median age of 5.7 years (range: 0.6-20). Overall, 41 survivors (16.5%) never attended LTS clinic. These included 15 survivors (6.0%) that were seen for initial disease follow-up after EOT but had no further contact with the hospital system beginning 2 years after EOT. In adjusted models, older age at EOT was associated with a higher likelihood of never attending LTS clinic (p<0.001). For example, survivors age 15 years and older at EOT were 7.4-times more likely to never attend LTS clinic (95% CI: 1.95-28.24). Additionally, compared with privately insured survivors, those with public insurance (OR=4.09, 95% CI: 1.67-9.99) and those that were uninsured (OR=4.68, 95% CI: 0.69-31.52) were more likely to never attend LTS clinic. LTS clinic attendance was largely comparable regardless of diagnosis, treatment exposures, sex, primary household language, and race/ethnicity, although Latinos were less likely to never attend an LTS visit compared with non-Latino whites (OR=0.36, 95% CI: 0.14-0.94). These observed associations were also independent of estimated travel time and neighborhood-level SDOH. Clinical and demographic factors provided reasonable predictive performance (AUC-ROC: 0.733, 95% CI: 0.655-0.821), e.g., categorizing survivors on their predicted probability of never attending LTS clinic based on observed clinical and demographic factors correctly identified 63.4% of survivors who never attend LTS clinic in the upper tertile of the risk prediction distribution. Conclusions: Texas has the highest rates of uninsured children in the United States, comprising 12.7% of all children and 17.5% of Latino children living in the state (2019 American Community Survey data). Moreover, Medicaid eligibility in Texas is significantly limited for adults between the ages of 18 and 65 years. In this study, both older age at EOT and public insurance or uninsured status at EOT were strongly predictive of no documented LTS care among survivors of childhood leukemia, suggesting health insurance is major limiting factor to accessing survivorship services in Texas. Limiting predictive factors to race/ethnicity, age at EOT and payer status at EOT provides reasonable prediction of leukemia survivor that do not engage in LTS care (AUC-ROC: 0.711). Validation of a simple risk prediction model using information readily available in the electronic medical record at EOT may inform targeted interventions to augment access to survivorship services in this vulnerable population.

Epigenetic Age Acceleration and Risk for Chronic Health Conditions in a Diverse Cohort of Survivors of Childhood Acute Lymphoblastic Leukemia

Background: Survivors of childhood cancer are at risk for multiple treatment related morbidities, including the early onset of chronic health conditions (CHC) that are late effects of cancer treatment. Epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm)-predicted age in excess of chronologic age, characterizes survivors of childhood cancer vs. controls that have no cancer history and is suggestive of premature, accelerated aging in this population. Further, among these survivors, greater EAA is associated with cardiometabolic, pulmonary, and neurologic late effects of cancer treatment. We examined the relationship between EAA and CHC in a diverse cohort of survivors of childhood leukemia, to better understand the impact of DNAm on outcome disparities. Approach: The study population included survivors of acute lymphoblastic leukemia (ALL) diagnosed at Texas Children's Hospital between 1992 and 2013 and seen at least once in the Texas Children's Cancer Center Long-Term Survivor Clinic. Demographics, diagnosis, treatment data, and date of onset and type of CHC were abstracted from the electronic health record. CHCs were defined as diagnoses attributed to the patient in the medical record and present for ≥ 1 year. CHCs were categorized by system. Germline DNA was obtained from survivors at least one year off therapy, and analyzed on an iScan System by Illumina MethylationEPIC BeadChip array in the Baylor College of Medicine Lab for Translational Genomics. Methylation data were processed using minfi, normalized with noob, and EAA estimated using the Horvath calculator. Clinical determinants of EAA were identified overall and at specified time periods after the completion of therapy using multivariable linear regression. The relationship between EAA and CHCs were assessed by multivariable Cox regression in a subset of Hispanics and non-Hispanic White (NHW) survivors. All analyses were adjusted for age at diagnosis, age at follow-up, Hispanic ethnicity yes/no, alkylator yes/no, anthracycline yes/no, and cranial radiation therapy (CRT) yes/no. Results: Cases included 268 survivors of ALL: 174 Hispanic, 156 NHW, 29 Black, 6 Asian, and 3 multi-racial. Younger age at diagnosis was associated with endocrine CHC (OR 0.84, 95% CI 0.70, 1.00) and neuropsychiatric CHC, specifically communication disorder (OR 0.82, 95% CI 0.67, 1.00). Older age at diagnosis was associated with obesity (OR 1.14, 95% CI 1.02, 1.28) and depression (OR 1.16, 95% CI 1.02, 1.33). Hispanics were more likely than NHW to have communication disorder (OR 2.92, 95% CI 1.03, 8.27) and learning disability (OR 2.48, 95% CI 1.03, 5.98). EAA was estimated in 171 samples obtained from 96 Hispanics and 75 NHW that were an average of 9.0 years from diagnosis (range: 1.3-21.9y) and stratified into time periods in survivorship: 3-7 years from diagnosis (n=53), 7-13 years from diagnosis (n=73), and >13 years from diagnosis (n=32). CRT was the only factor associated with EAA, including at both the early (beta 3.30, SE 1.31) and late (beta 5.13, SE 1.71) time points. Although EAA did not differ significantly between Hispanics and NHW, Hispanics exposed to CRT demonstrated a more than 4 year increase in EAA (beta=4.47 EAA years, p-value=0.0002), with a null effect on EAA in NHW (Table 1). The relationship between EAA and CHC differed in early vs. late survivorship. In adjusted analyses, EAA determined from samples obtained 3-7 years from diagnosis was associated with any neuropsychiatric CHC, and specifically with learning disability (HR: 1.44, 95% CI: 1.10, 1.87). In contrast, EAA determined from samples obtained >7 years from diagnosis was associated with a greater risk for obesity (HR: 1.21, 95% CI: 1.04, 1.42) and a lower risk for osteopenia (HR: 0.83, 95% CI: 0.70, 0.98). Conclusions: Results from this study confirm prior work indicating an association between EAA and risk for CHC in survivors of childhood cancer. In addition, our findings indicate that the relationship between EAA and specific CHC changes in early vs. late survivorship. Moreover, EAA results in Hispanics vs. NHW suggest a differential response to treatment exposures by survivor ethnicity, specifically with respect to CRT. Future directions of this work include validation of these findings in a diverse, multi-institutional survivor cohort. Table 1: Linear regression model of EAA in Hispanic and Non-Hispanic White survivors of ALL Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Physical Inactivity as an Early Sign of Frailty in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia.

Young adult survivors of childhood leukemia have been reported with increased likelihood of age-related comorbidities compared with the general population. We compared the prevalence of frailty in young adult survivors of childhood acute lymphoblastic leukemia (n=58, median age=23y, median survival time=18y) with age-matched and sex-matched controls without history of cancer. Frailty phenotypes were determined using Fried frailty model. Association between frailty status and cardiometabolic conditions, systemic inflammation, and T-cell immunophenotype changes were also examined. Frailty and prefrailty were more common among survivors compared with controls (58.6% vs. 34.5%, P =0.019). Physical inactivity (39.7%) was the most frequently observed frailty criterion among the survivors. Prevalence of cardiometabolic conditions was comparable between the robust and frail/prefrail survivors. Robust survivors had a higher level of T-cell activation than the prefrail/frail survivors ( P <0.05), but no significant difference was observed for systemic inflammatory markers (IL-6 and C-reactive protein) and percentage of terminally differentiated T cells. Signs of frailty, especially physical inactivity, was detected in childhood acute lymphoblastic leukemia survivors early in their third decade of life. Survivors who were prefrail/frail also had altered T-cell activation; however, the role of such changes in T-cell phenotype in the etiology of frailty warrant further investigation.