Adult Survivors Of Acute Lymphoblastic Leukemia Research Articles

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.

Low Bone Mass and Osteoporosis in Hispanic Acute Lymphoblastic Leukemia Survivors. Is It a Real Problem ?

Introduction: The survival rates in children and adolescent or young adults with acute lymphoblastic leukemia (ALL) have improved in the last decades. Cancer survivors can have reduced bone mineral density (BMD) related both to the underlying disease and the treatment. This can persist for up to 20 years, increasing the risk of osteopenia / osteoporosis and the development of fractures that can generate disability and loss of function. The risk factors for the development of disorders of BMD in the adult ALL survivors has been little studied and there are no formal guideline recommendations on the long-term follow-up and treatment of these patients. We evaluated ALL-survivor patients in Mexico; both ALL and osteoporosis are more prevalent in Hispanic patients, therefore we implemented conducting a dual-energy x-ray absorptiometry (DXA) during follow-up.Primary objective: Our main objective was to know the prevalence of alterations in bone mineral density (BMD) in a cohort of Hispanic ALL-survivors. Secondary objectives: To identify risk factors and the incidence of complications associated with BMD alterations.Methods: An observational, case-control study in a cohort of adult ALL survivors with follow-up at a referral center´s acute leukemia clinic in Mexico City. We include patients with more than one year of elective cessation of treatment in whom a DXA was performed as the routine follow-up for survivors. We compared the characteristics of the cases (patients with alterations in BMD) with the controls (patients without alterations in BMD). We define alterations in BMD by the WHO and the International Society of clinical DXA: the term of low BMD was used for younger patients and osteoporosis/osteopenia for older.Results: 61 ALL survivors were identified, 86.9% had B-Cell ALL and 13.1% T-Cell ALL. The median age at diagnosis was 12 years (1-55 years) and at the time of the study, 27 years (20-69 years). The majority (78.8%) had less than 18 years-old at diagnosis. The median follow-up from treatment cessation to densitometry was 142 months (10-499 months).An alteration in BMD was found in 63.9% of the patients: 84.6% were classified as low BMD for age and 15.4% as osteopenia/osteoporosis. The most frequently affected site was the spine (40%) followed by the hip and spine (32.5%) and the hip (10%). The median T-score and Z-score by area are shown in Table 1.Table 2 shows the characteristics of ALL-survivors with or without alterations in BMD. The median follow-up time was not different between the 2 groups. Gender, age at diagnosis, the use of induction dexamethasone and other chemotherapeutic agents, vitamin D deficiency, and hypogonadism were not associated with an increased risk of alterations in BMD. Receiving induction chemotherapy between 8 and 18 years of age (age where the highest bone mass is acquired) does not affect in the BMD at follow-up.During follow-up, three patients developed fractures: one pathological and 2 associated with trauma. The patient with a pathological fracture is a man with ALL diagnosed at 8 years of age and had an ankle fracture at 12 years associated with osteoporosis.Discussion and Conclusions:Alterations in BMD are very frequent in our cohort of ALL-survivors despite being a very young population (90% are under 50 years of age). We could not replicate the classically associated risk factors for altered BDM. We only found a non-significant trend for hematopoietic-stem cell transplantation (HSCT) and radiotherapy. This was previously been associated with alterations in different hormonal axes. Despite the high-prevalence of alterations in BMD, the incidence of fractures is very low. This may be related to the fact that it is unknown how to interpret DXA in a group of patients who received chemotherapy/radiotherapy in growth stages. Despite the limitations (small number of patients, the time between treatment and densitometry is heterogeneous and hormonal axes are not measured in all patients), given the high prevalence of BMA alterations, a better understanding of DXA findings in this group of patients is needed. [Display omitted] DisclosuresRangel-Patiño: Bristol: Consultancy; Abbvie: Speakers Bureau. Demichelis: AMGEN: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Bristol/Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; ASH: Research Funding; Gilead: Consultancy; Abbvie: Consultancy, Speakers Bureau.

DIVERGT screening procedure predicts general cognitive functioning in adult long-term survivors of pediatric acute lymphoblastic leukemia: A PETALE study.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Because of major improvements in treatment protocols, the survival rate now exceeds 80%. However, ALL treatments can cause long-term neurocognitive sequelae, which negatively impact academic achievement and quality of life. Therefore, cognitive sequelae need to be carefully evaluated. The DIVERGT is a battery of tests proposed as a screening tool, sensitive to executive function impairments in children and adolescent cancer survivors. Our study aimed at verifying the predictive value of the DIVERGT on general cognitive functioning in adult long-term survivors of ALL. ALL survivors completed the DIVERGT 13.4 years, on average, after remission (N=247). In addition, 49 of these survivors (equally selected amongst those with low, average, and high DIVERGT scores) as well as 29 controls completed a more comprehensive neuropsychological evaluation within a 3-year period from DIVERGT administration. Multivariate regression analysis was used to assess the predictive value of the DIVERGT on general intelligence, mathematics, verbal memory, and working memory. As a follow-up analysis, three performance groups were created based on the DIVERGT results. Multivariate analysis of variance (MANOVA) assessed neuropsychological differences between groups. The DIVERGT accurately predicted General Ability Index (GAI) (P<0.0001), mathematics (P<0.0001) and verbal memory (P=0.045). Moreover, the low-performance group consistently had poorer performance than the high-performance and control groups on the neuropsychological tests. The DIVERGT is a useful, time-effective screening battery for broader neurocognitive impairments identification in long-term adult ALL survivors. It could be implemented as routine examination in cancer follow-up clinics.

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.

Comparison of mandibular cortical thickness and QCT-derived bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia: a retrospective study.

To examine whether panoramic radiograph-determined mandibular cortical thickness correlated with quantitative computed tomography-derived bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia (ALL). We identified patients treated for ALL at St. Jude Children's Research Hospital, seen in the After Completion of Therapy (ACT) Clinic between January of 2006 and January of 2014 who had QCT-derived BMD and panoramic radiographs obtained within 1 month of each other. Panoramic radiographs were independently scored by a pediatric radiologist, two pediatric dentists, and a general dentist using the Klemetti technique. We used the Spearman's rank correlation test and the multivariate regression model to investigate the effect of evaluator experience on results. The study cohort comprised 181 patients with 320 paired studies: 112 (62%) male, 112 (71%) were white. Median age at ALL diagnosis was 6.4 (range, 0-18.8) years. Median age at study was 11.9 (range, 3.3 to 29.4) years. The median average BMD was 154.6 (range, 0.73-256) mg/cc; median QCT Z-score (age and gender adjusted) was -0.875 (range, -5.04 to 3.2). We found very weak association between panoramic radiograph score and both QCT-BMD average (P = 0.53) and QCT Z-score (P = 0.39). Results were not influenced by level of reader experience. The Klemetti technique of estimating BMD does not predict BMD deficits in children and young adult survivors of ALL, regardless of reviewer expertise. Alternative methods are needed whereby dental healthcare providers can identify and refer patients at risk for BMD deficits for detailed assessment and intervention.

Treatment, behavioral, and psychosocial components of cardiovascular disease risk among survivors of childhood and young adult cancer.

The incidence of childhood, adolescent, and young adult (AYA) cancers have been increasing since 1975.[1][1] In 2014, an estimated 10 450 and 5330 new cancers will be diagnosed among children aged birth–14 and adolescents aged 15 to 19 years old, respectively.[2][2] For young adults aged 20 to 34

Regional brain glucose metabolism and neurocognitive function in adult survivors of childhood cancer treated with cranial radiation.

The objective of this study was to examine associations between regional brain metabolism, as measured by (18)F-FDG PET, and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation. Thirty-eight adult survivors of ALL were randomly selected from a large cohort treated with cranial radiation therapy (19 with 18 Gy and 19 with 24 Gy of exposure). At a mean age of 26.4 (range, 22.3-37.4) years, and 23.5 (range, 20.4-32.8) years since diagnosis, patients underwent comprehensive neurocognitive evaluations and brain (18)F-FDG PET imaging during a resting condition. (18)F-FDG PET images were analyzed stereotactically, and pixel values were normalized to global activity. Predefined region-of-interest and voxel-based correlation analyses were performed. Compared with national norms, survivors demonstrated lower vocabulary (P < 0.001), reading (P < 0.001), mathematics (P < 0.001), working memory (P < 0.001), oral naming speed (P < 0.001), and cognitive flexibility (P < 0.001). Metabolic activity was higher in basal gangliar structures for those treated with 24 Gy of cranial radiation therapy (P = 0.04). Metabolic activity was positively correlated with oral naming speed in both lateral frontal lobes (ρ = 0.48 and 0.47 for right and left frontal regions, respectively, P < 0.01) and negatively correlated with cognitive flexibility in the sections of the basal ganglia (P < 0.01 for both caudate and putamen). Neurocognitive impairment in long-term survivors of ALL treated with cranial radiation appears to be associated with increased metabolic activity in frontal cerebral cortical and subcortical regions in the basal ganglia, suggesting decreased efficiency of the frontostriatal brain circuit.

Calcium and cholecalciferol supplementation provides no added benefit to nutritional counseling to improve bone mineral density in survivors of childhood acute lymphoblastic leukemia (ALL)

We sought to improve lumbar spine bone mineral density (LS-BMD) in long-term survivors of childhood acute lymphoblastic leukemia (ALL) using calcium and cholecalciferol supplementation. This double-blind, placebo-controlled trial randomized 275 participants (median age, 17 [9-36.1] years) with age- and gender-specific LS-BMD Z-scores <0 to receive nutritional counseling with supplementation of 1,000 mg/day calcium and 800 International Unit cholecalciferol or placebo for 2 years. The primary outcome was change in LS-BMD assessed by quantitative computerized tomography (QCT) at 24 months. Linear regression models were employed to identify the baseline risk factors for low LS-BMD and to compare LS-BMD outcomes. Pre-randomization LS-BMD below the mean was associated with male gender (P = 0.0024), White race (P = 0.0003), lower body mass index (P < 0.0001), and cumulative glucocorticoid doses of ≥ 5,000 mg (P = 0.0012). One hundred eighty-eight (68%) participants completed the study; 77% adhered to the intervention. Mean LS-BMD change did not differ between survivors randomized to supplements (0.33 ± 0.57) or placebo (0.28 ± 0.56). Participants aged 9-13 years and those 22-35 years had the greatest mean increases in LS-BMD (0.50 ± 0.66 and 0.37 ± 0.23, respectively). Vitamin D insufficiency (serum 25[OH]D <30 ng/ml) found in 296 (75%), was not associated with LS-BMD outcomes (P = 0.78). Cholecalciferol and calcium supplementation provides no added benefit to nutritional counseling for improving LS-BMD among adolescent and young adult survivors of ALL (93% of whom had LS-BMD Z-scores above the mean at study entry).

Dexamethasone exposure and memory function in adult survivors of childhood acute lymphoblastic leukemia: A report from the SJLIFE cohort

Dexamethasone is used in acute lymphoblastic leukemia (ALL) treatment, though long-term impact on central nervous system (CNS) function is unclear. As glucocorticoids influence hippocampal function, we investigated memory networks in survivors of childhood ALL treated with dexamethasone or prednisone. Neurocognitive assessment and functional magnetic resonance imaging (fMRI) were conducted in 38 adult survivors randomly recruited from cohorts treated on one of two standard treatment protocols, which differed primarily in the glucocorticoid administered during continuation therapy (dexamethasone [n = 18] vs. prednisone [n = 20]). Groups did not differ in age at diagnosis, age at evaluation, or cumulative intravenous or intrathecal methotrexate exposure. Survivors treated with dexamethasone demonstrated lower performance on multiple memory-dependent measures, including story memory (P = 0.01) and word recognition (P = 0.04), compared to survivors treated with only prednisone. Dexamethasone treatment was associated with decreased fMRI activity in the left retrosplenial brain region (effect size = 1.3), though the small sample size limited statistical significance (P = 0.08). Story memory was associated with altered activation in left inferior frontal-temporal brain regions (P = 0.007). Results from this pilot study suggest that adult survivors of ALL treated with dexamethasone are at increased risk for memory deficits and altered neural activity in specific brain regions and networks associated with memory function.

Long-Term Memory Deficits and Early Onset Dementia in Aging Adult Survivors of Childhood Acute Lymphoblastic Leukemia Treated with Cranial Irradiation

AbstractAbstract 664 Background:Survivors of childhood acute lymphoblastic leukemia (ALL) who received prophylactic cranial radiation therapy (CRT) are at increased risk for deficits in neurocognitive skills, including attention, working memory and processing speed. As survivors age, global brain injury from CRT may reduce cognitive reserve, placing them at risk for early onset dementia or long-term memory deficits. The prevalence of dementia and memory abnormalities in adult survivors of childhood ALL has not previously been established. Methods:Analyses were conducted on 265 of 445 (60%) eligible survivors of childhood ALL (median age 36 years, range 26–54 years; 52% female) treated with 18Gy (n=127) or 24Gy (n=138) CRT with a median time from CRT of 30 years (range 15–46 years). Participants completed the Wechsler Memory Scale IV, including the Brief Cognitive Status Exam (BSCE), and the Wechsler Abbreviated Scale of Intelligence (WASI). Age-adjusted standard scores were calculated and the BSCE was also adjusted for education level. Prevalence of memory impairment (<1 SD below age-expected mean), stratified by RT dose exposure, is reported and logistic regression used to identify risk factors for impairment. A subset of survivors (n=85) completed brain magnetic resonance imaging (MRI), including assessment of hippocampal volume, cortical thickness, white matter volume, diffusion tensor imaging, and functional MRI (fMRI) during a cued-recall memory task. Results:Survivors who received 24 Gy CRT had increased impairment on global measures of both short-term recall (33%; p<0.001) and long-term recall (30%; p<0.001), while no increase in impairment was seen after 18Gy. Impaired short-term recall was associated with smaller right (p=0.02) and left (p<0.01) temporal lobe volumes, while impaired long-term recall was associated with thinner parietal and frontal cortices. On subtests evaluating narrative memory (i.e. story recall) and design memory, increasing RT dose (24 vs. 18Gy) was associated with an increased prevalence of long-term memory impairment (narrative: 28% vs. 12%, p=0.001; designs: 13% vs. 3.2%, p=0.003). However, no CRT dose response was identified for short term narrative and design memory. Survivors with impaired long-term memory for designs demonstrated a compensatory increase in left hippocampal fMRI activation (p=0.005), and the effect was greater in the higher dose group (p = 0.04). The mean score for long-term narrative memory among survivors who received 24Gy was equivalent to the mean score of a 70–74 year old adult population. Neither young age (0–4 years) at CRT (Odds Ratio [OR] 1.4, 95% confidence interval [CI] 0.8–2.7), time from CRT (OR 1.0, 95% CI 0.9–1.1) nor intrathecal methotrexate exposure (OR 3.9, 95% CI 0.4–36.1) were significantly associated with long-term memory deficits. Reduced cognitive status (by BSCE) was identified after 18Gy (9%, p=0.11) and 24Gy (18%, p<0.001), suggesting a CRT dose-response effect. On diffusion tensor imaging, increased radial diffusivity in the frontal, parietal and temporal regions, an inverse measure of white matter integrity, was associated with reduced BSCE. Current employment rates were equivalent (63%) in both CRT dose groups, suggesting no difference in functional status. Conclusions:Aging adult survivors of ALL who received 24Gy CRT have reduced cognitive status and significant impairment in short-term and long-term memory. There appears to be a dose response effect selective for long-term narrative and design memory, but not for short term narrative and design memory. These patterns are consistent with early onset of age-related (long-term) memory loss, and early stage dementia, yet at a median age of only 36 years. After 24Gy, survivors have the narrative memory equivalent to a 70 year-old in the general population. Survivors with memory impairment demonstrated reduced integrity on structural and functional neuroimaging in anatomical regions established as essential for memory formation and long-term recall. However, these memory impairments do not seem to affect functional status (employment rates) suggesting that, rather than frank dementia, deficits in middle adulthood are consistent with mild cognitive impairment (MCI). Longitudinal evaluation of this population is needed as MCI often progresses into early onset dementia with age. Disclosures:No relevant conflicts of interest to declare.

Quality of Life Following Completion of Treatment for Adult Acute Lymphoblastic Leukemia with a Pediatric-Based Protocol.

Abstract 2567 Background:The use of pediatric-based protocols in the management of adult acute lymphoblastic leukemia (ALL) appears to result in improved survival, particularly in young adults. However, significant treatment-related toxicities have been identified with these regimens, including osteonecrosis and peripheral neuropathy. These are potentially disabling and can adversely affect quality of life (QoL); however, the long-term impact of such treatment regimens on health-related QoL in this adult population has not previously been reported. We therefore aimed to assess various dimensions of QoL in long-term survivors of adult ALL following treatment with a modified Dana Farber Cancer Institute 91-01 pediatric protocol, which is used as standard frontline therapy in our institution. Methods:QoL was self-reported using 5 psychometrically validated instruments: the EORTC QLQ-C30, the Functional Assessment of Cancer Therapy fatigue subscale (FACT-F), the Brief Pain Inventory, the Subjective Peripheral Neuropathy Screen (SPSS), and the 9-item Patient-Health Questionnaire (PHQ-9). Standard analyses of each instrument were conducted. Where available, results were compared to published population normative data. Results:29 patients (median age 41 years, range 21–64, 90% male), in continuous complete remission at a median of 28 months following completion of the two-year treatment protocol, were enrolled between March 2010 - April 2012. In comparison to reference data from a general population, the mean global health score on the EORTC QLQ-C30 was similar (p=0.68), but leukemia survivors had lower cognitive (p<0.001) and social (p<0.001) function scores, as well as more marked financial difficulty (p<0.001). The most prevalent and severe of the symptom items assessed by the EORTC QLQ-C30 were fatigue and pain, both of which showed significant inverse correlation with global health status and all functional scales (physical, role, emotional, cognitive, and social). Some degree of fatigue was reported by 83% of patients. Evaluation by FACT-F revealed worse fatigue scores for leukemia survivors compared with the general population (p=0.03). Mean pain intensity was higher in those more than 24 months from completion of treatment, vs. < 24 months (p=0.04). In the 9 patients (31%) experiencing moderate-severe pain, the most common sites were joints and neck/back. Of the 10 patients reporting regular use of analgesics, 4 were using opioids. The SPSS identified 12 patients (43%) with moderate or severe symptoms associated with peripheral neuropathy (burning, paraesthesias and/or numbness), mostly affecting the lower extremities. Neuropathy was more severe in patients over age 40 (p<0.01). The PHQ-9 identified 4 patients (14%) with significant depressive symptoms. Conclusions:Long-term adult ALL survivors who were treated with a pediatric-based regimen generally do well in terms of global QoL. However, fatigue, joint-related pain and neuropathy symptoms are common and can negatively affect QoL. Impairments in the domains of cognitive function and social function, as well as the prominence of financial hardship in this population, are findings that warrant further exploration. Disclosures:No relevant conflicts of interest to declare.

Increased prevalence of risk factors for cardiovascular disease in long‐term survivors of acute lymphoblastic leukemia and Wilms tumor treated with radiotherapy

Only a few studies have assessed cardiovascular risk factors (CRFs) in childhood cancer survivors. We determined the prevalence of CRFs in long-term survivors of acute lymphoblastic leukemia (ALL) and Wilms tumor. Adult survivors of ALL and Wilms tumor treated with radiotherapy and chemotherapy (RT + CT) or treated with chemotherapy alone (CT) were compared with sibling controls. CRFs (hypertension, diabetes mellitus, hypercholesterolemia, obesity, renal insufficiency) and hormonal deficiencies were assessed in each participant. Multivariate logistic regression analysis was used to evaluate the association between CRFs and treatment. Seventy-nine ALL, 62 Wilms tumor survivors, and 69 control subjects (mean ages 24.5, 25.9, and 26 years, respectively) were enrolled. Mean follow-up time since cancer treatment was 20.8 years. In the Wilms RT + CT group significantly more survivors had hypertension (21.6% vs. 1.4%, P < 0.001) and renal insufficiency (8.1% vs. 0%, P = 0.016) compared to controls. There were also more patients with multiple CRFs in the Wilms RT + CT group (16.2% vs. 2.9% in controls, P = 0.019). Almost 15% of ALL RT + CT survivors had growth hormone deficiency. Hypogonadism was seen in 18.9% of survivors in the Wilms RT + CT group. We observed no significant differences between CT-treated survivors of both malignancies and controls. The adjusted odds ratio for the occurrence of at least one CRF was 2.6 increased for survivors following abdominal radiotherapy. Treatment with CT alone was not associated with the occurrence of multiple CRFs. Long-term survivors of ALL and Wilms tumor have unfavorable CRFs due to previous RT not CT.

ARTERIAL FUNCTION IN YOUNG ADULTS AFTER CHEMOTHERAPY DUE TO ACUTE LYMPHOBLASTIC LEUKEMIA- PILOT STUDY: PP.6.235

Objective: Survivors of childhood cancer have increased cardiovascular (CV) morbidity and mortality possibly related to anticancer treatment. Therefore, we assessed CV risk profile and arterial function in the young adults with acute lymphoblastic leukemia (ALL) in whom chemotherapy was completed at least five years ago. Methods: Young (age: 18–30 years) survivors of ALL were invited for assessment of CV risk factors and arterial function. Medical history, physical examination with anthropological measurements, ambulatory blood pressure monitoring; levels of fasting glucose (FG), cholesterol, fibrinogen, hsCRP were measured. Arterial function was assessed using endothelium dependent flow-mediated dilatation (FMD%) of right brachial artery and carotid -femoral pulse wave velocity (PWV). Results: We present preliminary results of 14 subjects (7 men, age: 21,4 ± 3,08) years) who agreed to participate in the study. Mean BMI was 22(2,01) and WHR 0,79(0,06). 24-hour mean BP was 116,8(7,2)/68,3(4,7) mmHg. The values of laboratory findings were: FG: 4,6(0,3) mmol/l, hsCRP: 0,83(1,2) mg/l, TC: 4,28(0,8) mmol/l, LDL: 2,28(0,7) mmol/l, HDL: 1,57(0,4) mmol/l, TG: 0,97(0,48) mmol/l, fibrinogen: 3,1(0,5) g/l. Five subjects presented with 1 or more CV risk factors such as smoking (4), positive family history of CVD (2), hypercholesterolemia (2), masked hypertension (1). Patients had a mean basal brachial artery diameter of 3,40 ± 0,67 mm. Mean FMD response was 5,74 ± 5,99 % and reactive hyperemia: 51,66 ± 28,25%, the percent change in nitrogliceryne mediated dilatation was 23,36 ± 10,12%. 9 (64%) participants had FMD < 10% and 7 < 7%. When 9 subjects without CV risk factors were analysed in 6 of them FMD was found to be below 10% and in 5 < 7%. Mean PWV was 8,03(0,81) m/s and in 9 subjects exceeded 8 m/s. Moreover, PWV was increased in 4 out of 9 subjects without CV risk factors. Conclusions: These preliminary results indicate that even in the absence of major cardiovascular risk factors young adult survivors of ALL demonstrate impaired endothelial function and increased arterial stiffness.

Voxel-based morphometry and diffusion-tensor MR imaging of the brain in long-term survivors of childhood leukemia

The aims of this study were to detect morphological changes in neuroanatomical components in adult survivors of acute lymphoblastic leukemia (ALL). Voxel-based morphometry (VBM) can be used to detect subtle structural changes in brain morphology and via analysis of fractional anisotropy (FA), diffusion-tensor imaging (DTI) can non-invasively probe white matter (WM) integrity. We used VBM and DTI to examine 20 long-term survivors of ALL and 21 healthy matched controls. Ten ALL survivors received chemotherapy and irradiation; ten survivors received chemotherapy alone during childhood. Imaging was performed on a 3.0-T MRI. For VBM, group comparisons of segmented T1-weighted grey matter (GM) and WM images from controls and ALL survivors were performed separately for patients who received chemotherapy alone and who received chemotherapy and irradiation. For DTI, FA in WM was compared for the same groups. Survivors of childhood ALL who underwent cranial irradiation during childhood had smaller WM volumes and reduced GM concentration within the caudate nucleus and thalamus. The FA in WM was reduced in adult survivors of ALL but the effect was more severe after combined treatment with irradiation and chemotherapy. Our results indicate that DTI and VBM can reveal persistent long-term WM and caudate changes in children after ALL treatment, even without T2 changes in conventional imaging.

Childhood Leukemia Survivors At Risk for Harmful Obesity

Endocrinology| January 01 2008 Childhood Leukemia Survivors At Risk for Harmful Obesity AAP Grand Rounds (2008) 19 (1): 5. https://doi.org/10.1542/gr.19-1-5 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Childhood Leukemia Survivors At Risk for Harmful Obesity. AAP Grand Rounds January 2008; 19 (1): 5. https://doi.org/10.1542/gr.19-1-5 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: childhood leukemia, obesity, survivors, leptin, insulin-like growth factor i, leukemia, lymphocytic, acute, childhood Source: Janiszewski PM, Oeffinger KC, Church TS, et al. Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab. 2007;92(10):3816–3821; doi:10.1210/jc.2006–2178 Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, has an overall cure rate of approximately 80%.1 Long-term survivors of childhood ALL are at increased risk for obesity, cardiovascular disease, and related mortality in the years following treatment.2 Investigators from multiple US institutions studied young adult survivors of ALL to assess the association of cranial radiotherapy (CRT) with levels of total, regional, and ectopic fat storage, metabolic risk, IGF-1, and leptin. A total of 237 young adult survivors of childhood ALL, treated from 1970–2000 in the Dallas-Fort Worth area, were identified. Of the 189 individuals who met eligibility criteria, 114 were enrolled and completed the study. Study participants’ mean age was 23.8 years, their mean age at diagnosis was 6.2 years, the mean interval from diagnosis to study enrollment was 17.5 years, and 23.7% were of an ethnic or racial minority group. Anthropometric measures, blood pressure, metabolic status, and levels of IGF-1 and leptin were assessed in 52 male (15 CRT-treated) and 62 female (24 CRT-treated) participants. Visceral, liver, and subcutaneous fat were determined using abdominal CT scan. Data from patients treated with CRT and non-CRT survivors were compared after controlling for potentially confounding variables. Exposure to CRT had no effect on BMI, waist circumference, or liver fat. Controlling for age and race, ALL survivors treated with CRT had significantly higher body fat percentage and more abdominal and visceral fat than non-CRT patients. IGF-1 levels were significantly lower and leptin levels significantly higher in the group that received CRT. There was more evidence of insulin resistance and dyslipidemias in CRT patients compared with the non-CRT survivors. The authors conclude that among ALL survivors CRT is associated with excess accumulation of abdominal fat, particularly visceral fat, and elevated metabolic risk. Dr. Varma has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Fortunately, we are seeing more and more long-term survivors of ALL. ALL survivors are at high risk for obesity,3 cardiovascular disease,4 and related mortality.2 CRT during ALL treatment has been shown to be the potential cause for excess weight gain among survivors.5 The authors of the current study suggest that treatment with CRT among ALL survivors is associated with increased plasma leptin levels, even when it is expressed per unit of fat mass. This observation indicates that obesity subsequent to treatment with CRT may be secondary to induced hypothalamic resistance to leptin. The abdominal and visceral obesity are warning signs for the metabolic syndrome. Since oncologists may not follow ALL survivors late into adolescence, primary care providers need to be aware of the sequelae of treatment, and monitor patients with a history of CRT for signs of obesity and other cardiovascular risks. (For discussions... You do not currently have access to this content.

Secondary or concomitant neoplasms among adults diagnosed with acute lymphoblastic leukemia and treated according to the LALA‐87 and LALA‐94 trials

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL. The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years. By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months. The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk.

Abdominal Obesity, Liver Fat, and Muscle Composition in Survivors of Childhood Acute Lymphoblastic Leukemia

Survivors of childhood acute lymphoblastic leukemia (ALL) become obese, and are at increased risk for morbidity and mortality post therapy. We determined the association of cranial radiotherapy (CRT) and/or sex with levels of total, regional, and ectopic fat storage, metabolic risk, IGF-I, and leptin in adult ALL survivors. A cross-sectional analysis of 52 male (15 CRT treated) and 62 female (24 CRT treated) young adult ALL survivors was conducted. We assessed levels of visceral fat, sc abdominal and thigh fat, and liver and muscle fat using computed tomography, total fat and lean body mass using dual-energy x-ray absorptiometry, and IGF-I and leptin levels by radioimmunoassay. Controlled for age and race, ALL survivors treated with CRT had higher levels of abdominal and visceral fat, body fat percentage, metabolic risk (insulin resistance and dyslipidemia), and leptin but lower lean mass and IGF-I levels than non-CRT survivors (P </= 0.05 for each). Levels of IGF-I were inversely associated with total, abdominal, and visceral fat in both sexes (P < 0.05 for each). Female ALL survivors had less lean mass and visceral fat but higher total and sc abdominal fat than males (P < 0.05 for each). Neither sex nor CRT was associated with muscle and/or liver fat content (P > 0.1). Among young adult ALL survivors, CRT is a risk factor for elevated total, abdominal, and visceral adiposity, a reduced fat-free mass, elevated metabolic risk, and altered IGF-I and leptin levels.

Exercise echocardiography reveals subclinical cardiac dysfunction in young adult survivors of childhood acute lymphoblastic leukemia

Anthracyclines (AC) have contributed significantly to increased survival rate in acute lymphoblastic leukemia (ALL), although the use of these drugs is limited due to cardiotoxicity. The aim was to evaluate heart muscle function in asymptomatic adult survivors of ALL treated in early childhood in relation to the combined effects of AC and other potential cardiotoxic factors. Twenty-three young adult ALL survivors who had all received treatment with median 120 (120-400) mg AC/m(2) before the onset of puberty were examined median 21 years after remission and compared with 12 healthy controls. Basal echocardiography including two-dimensional (2D) M-mode and Doppler examination was performed, followed by a maximal exercise stress test and stress echocardiography immediately after stress test and after 5 min recovery. We found significant differences in systolic function between patients and controls at maximal exercise despite absence of reported symptoms from the patients. The most marked difference was in ejection fraction at stress 59.5% (32.6-81.1) and 77.3% (66.2-85.3), respectively (P < 0.00006). Ten out of 23 patients reduced their ejection fraction at stress compared with at rest; this was not found in any of the controls. Cardiovascular risk factors such as GH deficiency and a high proportion of trunk fat did not have an impact on cardiac function. With very long follow up in a homogenous cohort of ALL survivors, we found subclinical cardiac dysfunction with exercise stress echocardiography even after low doses of AC.

Evaluation for cardiac toxicity with MRI in young adult survivors of acute lymphoblastic leukemia (ALL)

18604 Background: Long-term survivors of childhood cancer treated with a moderate to high cumulative dose (≥300mg/m2) an anthracycline are known to be at risk for cardiac toxicity. It remains unclear what cardiac risk exists for survivors who received a low cumulative dose (&lt;300mg/m2) of an anthracycline. Methods: We are conducting an NIH sponsored trial in 120 young adult survivors of ALL to determine the prevalence of cardiovascular risk factors and to determine the effectiveness of an exercise intervention. As part of their cardiovascular risk assessment, participants undergo cardiac MRI, a tool with excellent reproducibility in assessing left ventricular (LV) size and function. The aim of this component of the study is to determine the prevalence of cardiac toxicity in survivors treated with low dose anthracycline in comparison to those who did not receive any anthracycline. Descriptive statistics, chi-square analysis, and spearman correlation coefficients were used to examine the relationship between anthracycline dose and measures of cardiac function. Results: This study represents a work in progress. Preliminary results from the first 22 participants who have had a cardiac MRI do not show a significant difference in ejection fraction, LV mass, cardiac output, or mass to volume ratio between those treated with low cumulative dose anthracycline versus no anthracycline. Available cardiac MRI data for all participants will be presented at the meeting. Conclusions: With the continued use of an anthracycline at cumulative low doses, particularly in upcoming ALL standard risk trials, it is particularly important to determine if there is a risk of cardiac toxicity after low doses with aging. No significant financial relationships to disclose.

Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

Overweight (body mass index [BMI] 25 to 29 kg/m2) and obesity (BMI > or = 30 kg/m2) frequently follow treatment for childhood acute lymphoblastic leukemia (ALL). Recent studies suggest that risk is most apparent in females treated with cranial radiation at a younger age. Because radiation at a young age may affect the hypothalamus causing leptin receptor insensitivity, we hypothesized that a polymorphism in the leptin receptor (LEPR) gene, Gln223Arg, might influence susceptibility to obesity in survivors of childhood ALL. We genotyped 600 non-Hispanic white adult ALL survivors enrolled onto the Childhood Cancer Survivor Study. BMI was compared between those with two copies of the Arg allele to those who had at least one copy of the Gln allele. Female survivors with BMI > or = 25 kg/m2 were more likely Arg homozygous than those with BMI less than 25 kg/m2 (24% v 12%; P =.007). This difference was not observed in males. Moreover, among females treated with > or = 20 Gy cranial radiation, Arg/Arg individuals had six times higher odds of having BMI > or = 25 kg/m2 (95% CI, 2.1 to 22.0) than those with a Gln allele (P =.04 for interaction). CONCLUSION LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial radiation. Because obesity is associated with increased morbidity and mortality in later life, identification of children at high risk might allow for early targeted interventions.