Standard-risk Acute Lymphoblastic Leukemia Research Articles

Treatment outcome of childhood standard-risk and median-risk acute lymphoblastic leukemia with CCLG-2008 protocol

To estimate the significance of the adjustment of acute lymphoblastic leukemia (ALL) risk group by monitoring minimal residual disease(MRD). Totally 285 children ALL patients who were diagnosed and systematically treated according to CCLG-2008 in Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC, from April 2008 to August 2011 were prospectively selected. Among these cases, 62.8% (n = 179) were boys and 37.2% (n = 106) were girls and the median age was 5.3(0.5-14.0). The patients who were at high-risk group initially were excluded. The grouping of cases: the patients were divided into two groups according to the dates of initial diagnosis. Group I had 126 patients who were initially diagnosed between April 2008 and December 2009 in whom therapeutic regimen was not adjusted by reassignment of risk group by MRD. Group II had 159 patients who were initially diagnosed between January 2010 and August 2011 whose therapeutic regimen was adjusted by reassignment of risk group by MRD at specific time (33rd day of induction chemotherapy and 12 weeks after the beginning of chemotherapy). MP-FCM Coulter FC-500 was used in the detection of MRD. Among these 285 patients, 94.0% (n = 268) were diagnosed as B-lineage acute lymphoblastic leukemia and 6.0% (n = 17) were T-lineage acute lymphoblastic leukemia. In group I, 61.9% (n = 78) patients belonged to low-risk group, 38.1% (n = 48) median-risk; in group II, before the adjustment, the rates of the low-risk group and median-risk group were 68.6% (n = 109) and 31.4% (n = 50) , respectively, while after the adjustment they were altered to 53.5% (n = 85) and 39.6% (n = 63) , furthermore 6.9% (n = 11) patients went into the high-risk group. Both groups were followed up for 2.5 years after their diagnoses, the disease of 7.4% (n = 21) patients relapsed, and the rates of two groups were 12.7% (n = 16) and 3.1% (n = 5) respectively, P = 0.009. The rate of serious infection (such as sepsis, pulmonary infection) of all these patients was 32.3% (92/285) , there was no significant difference between the two groups [28.6% (36/126) vs.35.2% (56/159) , P = 0.392]. The mortality of all these patients was 6.7% (19/285) , and that of group I was higher than that of group II [10.3% (13/126) vs. 3.8% (6/159) , P = 0.044]. The 2.5 years overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) of group I were all lower than those of group II in Kaplan-Meier survivorship analysis (all P < 0.05). The two groups were followed up for 2.5 years after their diagnoses, after elimination of the confounding influence of sex, age, FAB subtype, WBC count, ratio of blast cells in bone marrow at diagnosed, chromosome karyotype and fusion gene, reassignment of risk group by MRD was used to calculate the OS, EFS and DFS of ALL patients (all P < 0.05). After the adjustment the risk group was more significant in the assessment of prognosis. The reassignment of risk group in low and median risk groups children with acute lymphoblastic leukemia by MRD did not increase the rate of serious infection but could reduce the relapse rate and mortality, and was beneficial to increase the patients' OS, EFS and DFS.

Prospective assessment of chemotherapy-induced peripheral neuropathy (CIPN) in children with standard-risk acute lymphoblastic leukemia (SR ALL): Results of Children’s Oncology Group (COG) AALL0932.

7056 Background: Vincristine is associated with CIPN that can impair daily function. Methods: Patients 3.0-9.9 years without neurological disorders, enrolled on ALL0932 at 26 sites, were evaluated ...

Superior Survival of Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Compared with Chemotherapy Alone Used as Post-Remission Therapy in Adults with Standard-Risk Acute Lymphoblastic Leukemia in First Complete Remission

We wanted to compare the efficacy of haploidentical hematopoietic stem cell transplantation (HSCT) with chemotherapy alone in adults with standard-risk acute lymphoblastic leukemia (ALL) in first complete remission (CR1). One hundred thirty-eight consecutive adult patients with standard-risk ALL in CR1 were retrospectively investigated. Of these patients, 59 received chemotherapy alone (group A) and 79 received unmanipulated haploidentical HSCT (group B). Cumulative incidence of relapse at 5 years in group A was significantly higher than that in group B (66.3% versus 29.9%, P < .0001). Overall and disease-free survival in group A were significantly inferior to group B (P < .0001). Moreover, multivariate analyses demonstrated that central nervous system leukemia (P = .002), T cell immunophenotype (P = .044), expression of E2A-PBX1 (P = .007), and positive minimal residual disease after the first cycle of consolidation (P = .004) were correlated with relapse. Patients with 1 of 4 risk factors were assigned to the high-risk group. Otherwise, patients without risk factors were assigned to the low-risk group. In the high-risk group, HSCT had lower relapse rates and superior DFS compared with chemotherapy (P < .05), but in the low-risk group, there were no differences between HSCT and chemotherapy (P > .05). This study is the first to demonstrate that compared with chemotherapy alone, haploidentical HSCT is a better postremission therapy in adults with standard-risk ALL in CR1. Moreover, based on the 4 risk factors, the establishment of risk stratification could identify the subgroup of patients with a higher risk of relapse in adults with standard-risk ALL in CR1. Furthermore, risk stratification–directed postremission therapies using haploidentical HSCT or chemotherapy alone not only reduce relapse rate but also avoid unnecessary treatment-related mortality and improve survival.

A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

The authors prospectively assessed anxiety, depression, and behavior in children with standard-risk acute lymphoblastic leukemia (SR-ALL) during the first year of therapy and identified associated risk factors. A cohort study was performed of 159 children (aged 2 years-9.99 years) with SR-ALL who were enrolled on Children's Oncology Group protocol AALL0331 at 31 sites. Parents completed the Behavior Assessment System for Children, the General Functioning Scale of the Family Assessment Device, and the Coping Health Inventory for Parents at approximately 1, 6, and 12 months after diagnosis. Overall, mean scores for anxiety, depression, aggression, and hyperactivity were similar to population norms. However, more children scored in the at-risk/clinical range for depression than the expected 15% at 1 month (21.7%; P= .022), 6 months (28.6%; P< .001), and 12 months (21.1%; P= .032). For anxiety, more children scored in the at-risk/clinical range at 1 month (25.2% vs 15%; P= .001), but then reverted to expected levels. On adjusted analysis, unhealthy family functioning was found to be predictive of anxiety (odds ratio [OR], 2.24; P= .033) and depression (OR, 2.40; P= .008). Hispanic ethnicity was associated with anxiety (OR, 3.35; P= .009). Worse physical functioning (P= .049), unmarried parents (P= .017), and less reliance on social support (P= .004) were found to be associated with depression. Emotional distress at 1 month predicted anxiety (OR, 7.11; P= .002) and depression (OR, 3.31; P= .023) at 12 months. Anxiety is a significant problem in a subpopulation of patients with SR-ALL immediately after diagnosis, whereas depression remains a significant problem for at least 1 year. Children of Hispanic ethnicity or those with unhealthy family functioning may be particularly vulnerable. These data suggest that clinicians should screen for anxiety and depression throughout the first year of therapy.

Everyday executive function in standard-risk acute lymphoblastic leukemia survivors

We aimed to evaluate parent-rated executive function (EF) in pediatric standard risk acute lymphoblastic leukemia (SR-ALL) survivors compared to a healthy comparison (HC) group. We hypothesized that SR-ALL survivors would have greater reported executive dysfunction compared to HC, and that those younger at the time of treatment would demonstrate greater EF difficulties. A sample of 256 SR-ALL survivors evaluated an average nine years after treatment were compared to HC matched for gender, assessment age, and maternal education. Profile analysis was used to compare the groups across EF scales on the BRIEF. The prevalence of clinical elevations in the groups was compared via chi square, and odds ratios were calculated. Regression models were applied to examine the role of age at diagnosis and age at assessment in reported EF. Results indicated that SR-ALL survivors’ mean scores of EF are similar to HC, except for flexibility and initiation. Survivors were rated as having clinical impairments with flexibility, initiation, working memory, and emotional control at rates two to three times that of HC. The risk of working memory and self-monitoring deficits was greater in survivors who were older when assessed. There was no relationship between age at diagnosis or treatment regimen on EF. These findings suggest sparing of extensive and severe EF deficits in SR-ALL survivors overall. However, a subset of survivors displays clinically significant executive dysfunction. There appears to be a heightened susceptibility to disrupted metacognitive functions as survivors age. This has implications for how we monitor neurocognitive development and functioning of SR-ALL survivors, and highlights opportunities for cognitive interventions.

The influence of detoxification agents on the intensity of side effects caused by medium-high doses of methotrexate in children with acute lymphoblastic leukemia: Case series

Objective The treatment of childhood acute lymphoblastic leukemia (ALL) in Serbia is conducted according to protocol ALL IC BMF-2009. The therapy includes the application of cytostatic drugs methotrexate and 6-mercaptopurine, and drug detoxifying Calcium Folinate. At the moment, 80% of affected children could be cured with current treatment, but resistance to the therapy and its toxic effects remain serious clinical problems. The aim of the study was to investigate the influence of detoxification agents (Calcium Folinate, silymarin and ursodeoxycholic acid) on the side effects of methotrexate, applied in this protocol. Methods A modified acute toxicity form (GPOH) was used for side effects monitoring. The research included children with either standard or intermediate risk ALL in the consolidation therapy phase, who were hospitalised at the Institute for Child and Youth Health Care of Vojvodina in Novi Sad during the period from July 2010 to February 2011. Results The most frequent side effect after 40 applications of methotrexate in ten children was bone marrow depression. Methotrexate caused: leukopenia in 10 patients, thrombocytopenia in 5 patients; after the use of folic acid, platelet count grew in 8 patients, leukocyte in 2 patients. Less frequent side effects: an increase serum transaminase activity, the state of fever, bronchopneumonia, diarrhoea with mild cramps and hypercalcaemia. Conclusion The application of Calcium Folinate, silymarin and ursodeoxycholic acid prevented the occurrence of severe adverse effects caused by medium-high doses of methotrexate. Observed adverse effects were of mild to moderate intensity, reversible and did not significantly disturb the quality of life in treated patients.

Excellent Event Free (EFS) and Overall Survival (OS) For Children With Standard Risk Acute Lymphoblastic Leukemia (SR ALL) Despite The Absence Of a Significant Impact On Outcome With The Addition Of An Intensified Consolidation: Results Of Children's Oncology Group (COG) AALL0331

▪The EFS/OS for SR (age 1-9.99 yrs and initial white blood cell count <50,000/microliter) B-cell precursor (B-ALL) patients (pts) has steadily improved over time. The COG AALL0331 SR ALL trial utilized a 3 drug induction without anthracylines, with post-induction assignment into refined risk groups (SR-Low, SR-Average (Av), SR-High) based on leukemia genetics and early response. COG studies have shown that intensified post-induction therapy improved EFS/OS in NCI high risk ALL patients <10 yrs of age; however, the relative value of individual components is uncertain. AALL0331 included a 2 X 2 randomization at end-induction to standard (SC) vs. intensified consolidation (IC) and standard interim maintenance (IM) / delayed intensification (DI) vs. intensified IM/DI for SR-Av (not Low or High) pts, defined as those whose leukemic blasts did not show triple trisomies (TT) of chromosomes 4+10+17, ETV6-RUNX1, or very high risk features and had an excellent early response based on day 8 (or 15) M1 (<5% blasts) bone marrow (BM) and end-induction minimal residual disease (MRD) <0.1%. The IM/DI randomization was closed in 2008 due to superior results of escalating IV methotrexate (MTX) during IM for SR ALL pts treated on CCG 1991; all pts subsequently received escalating IV MTX during IM.AALL0331 enrolled 5311 SR B-ALL pts from 4/2005-5/2010. All patients received a 3 drug induction (dexamethasone, vincristine (VCR), PEG-asparaginase (PEG), intrathecal (IT) MTX). SR-Av pts were randomized at end-induction between SC (mercaptopurine (MP) 75 mg/m2 d 1-28, VCR 1.5 mg/m2 d 1, IT MTX d 1, 8, 15) vs. IC (cyclophosphamide 1000 mg/m2 d 1,29, cytarabine 75 mg/m2 d 1-4, 8-11, 29-32, 36-39, MP 60 mg/m2 d 1-14, 29-42, VCR 1.5 mg/m2 d 15, 22, 43, 50, PEG 2500 units/m2 d 15, 43, IT MTX d 1, 8, 15, 22). Therapy following consolidation was the same for all SR-Av pts after 2008.The 5-yr EFS/OS for all evaluable SR B-ALL pts was 89% and 96% (see Table 1). IC did not significantly improve outcome for SR Av pts, with 5-yr continuous complete remission (CCR) rates for SC vs. IC of 88% (1.6%) vs. 89.3% (1.5%) (p=0.13) and 5-yr OS rates for SC vs. IC of 95.8% (1.0%) vs. IC 95.7% (1.0%) (p=0.93). Because COG has now shown that end-induction MRD of 0.01% is a better discriminator of poor outcome than the 0.1% level used in AALL0331, we examined overall outcome and the results of the randomized intervention in two different MRD defined subsets of SR-Av pts (Table 1). The 5-yr CCR rates for pts with MRD 0.01%-<0.1% were 77% (6%) and 76% (6%) for SC and IC (p=0.31) and 89% (1.6%) vs 91.5% (1.5%) for IC (p=0.08) for MRD <0.01%.Table 1Risk Group (# pts)5 year EFS (SE)5 year CCR (SE)5 year OS (SE)All pts (5192)89% (0.6%)96% (0.4%)SR-High (636)85% (2%)94% (1%)SR-Low (1857)95% (0.7%)99% (0.3%)SR-Av (1500)89% (1.1%)96% (0.7%)MRD <0.01% (1310)91% (1.2%)96% (0.6%)MRD >0.01-<0.1% (172)77% (4.5%)92% (3%)The outcome for the 1857 SR-Low pts (TT or ETV6-RUNX1 plus d 8 (or 15) M1 BM and d 29 MRD <0.1%) was outstanding, with 5-yr EFS/OS of 95% and 99%. SR-High pts (d 15 BM ≥5% blasts and/or d 29 MRD ≥0.1%) who were non-randomly assigned to IC and 2 intensified IM/DI phases did very well with 5-yr EFS/OS 85% and 94%. The 5-yr EFS for this group (85%) was much better than that of SR Av pts (77%) with MRD 0.01-<0.1% who received less intensive therapy, emphasizing the benefit of intensifying treatment for pts with MRD >0.01% that is now part of all COG protocols. COG AALL0331 is the largest trial of SR B-ALL pts ever conducted and establishes the value of risk directed treatment intensification. Disclosures:Matloub:Novartis: Consultancy.

Impaired B-cell reconstitution in children after chemotherapy for standard or medium risk acute precursor B-lymphoblastic leukemia

Chemotherapy for childhood acute lymphoblastic leukemia (ALL) is a highly effective treatment, but at the same time causes significant suppression of the patient's immunity. Immune reconstitution was studied in a homogeneous cohort of 48 children with standard or medium risk ALL treated according to the ALL-Berlin–Frankfurt–Münster (BFM) protocol. Whereas the T-cell compartment was only moderately affected and recovered to normal levels quickly after treatment cessation, B-cells were significantly reduced during and after therapy. In particular, the naive B-cell compartment declined. Even 5 years after the end of therapy, B-cell distribution was disturbed and patients showed an ongoing reconstitution. Thus, even standard regimens for chemotherapy cause severe B-cell depletion that resolves only gradually.

Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: Findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01

Dexamethasone is more efficacious than prednisone in the treatment of acute lymphoblastic leukemia (ALL), but has also been associated with greater toxicity. We compared neuropsychological outcomes for patients treated on DFCI ALL Consortium Protocol 00-01, which included a randomized comparison of the two steroid preparations during post-induction therapy in children and adolescents with ALL. Between 2000 and 2005, 408 children with standard-risk or high-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 00-01 were randomly assigned to prednisone or dexamethasone administered as 5-day pulses every 3 weeks for 2 years, beginning at week 7 of treatment. Blinded neuropsychological testing was completed for 170 randomized patients (prednisone, N = 76; dexamethasone, N = 94), all of whom were in continuous complete remission after completion of therapy. Outcomes were comparable for most variables, although patients on the dexamethasone arm performed more poorly on a measure of fluid reasoning (P = 0.02). They also tended to be more likely to be enrolled in special education (dexamethasone, 33% vs. prednisone, 20%, P = 0.09). Dexamethasone has well documented benefit in treatment of ALL. Although formal testing provided little indication of increased risk for neurotoxicity relative to prednisone, the somewhat greater utilization of special education services by patients treated with dexamethasone merits further investigation.

Outcome of childhood acute Lymphoblastic leukemia in Egyptian children: A challenge for limited health resource countries

In childhood acute lymphoblastic leukemia (ALL) the reported 5-year event-free survival (EFS) rates are as high as 80%. Since 2004, multiple Egyptian centers shifted protocol of therapy of ALL to the CCG 1991 (the single delayed intensification arm) and CCG 1961 protocol for standard risk and high-risk ALL therapy, respectively, being cost effective. We aimed to evaluate the efficacy and safety of the CCG protocol in treatment of childhood ALL in Ain Shams and Menoufeya University hospitals.MethodsFifty-two ALL patients, aged 1–17 years, treated according to the modified CCG protocol in both centers and registered from November 2004 to December 2005 were included. They were classified into three risk groups, standard risk (SR), high-risk standard arm (HR-SA), and high-risk augmented arm (HR-AA).ResultsThe mean age at diagnosis was 5.9 + 3.3 years, male/female ratio of 1.6:1, and central nervous system leukemia represented 6%. The 5-year overall survival (OS) and EFS were 84.6% and 67%, respectively. The 5-year OS and EFS were 92.6% and 70% in SR, 68.8% and 55% in HR-SA, 88.9% and 80% in HR-AA patients, respectively. Six patients had grade 3–4 adverse events.ConclusionThe outcome of HR-SA protocol was inferior to the other two groups, necessitating shift to a more intensified arm with double delayed intensification. The use of minimal residual disease for better risk classification of childhood ALL is recommended in our centers

Effect of dexamethasone (DEX) dose modification on osteonecrosis (ON) risk associated with intensified therapies for standard risk acute lymphoblastic leukemia (SR-ALL): A report from the Children’s Oncology Group (COG) study AALL0331.

10002 Background: ON is a known toxicity of childhood ALL therapy, particularly in patients (pts) &gt;9 years (y). Intensified use of DEX, methotrexate (MTX), and asparaginase (ASNase) may increase the risk of developing ON among B-precursor NCI SR-ALL pts despite their younger age. Methods: Newly diagnosed SR-ALL pts 1-9y enrolled on AALL0331 between 4/05 and 5/10 were prospectively monitored for symptomatic ON within three treatment cohorts risk-stratified by clinical, cytogenetic, and early response criteria. ON sites were confirmed by imaging. SR-Low (SRL) pts were randomized to standard therapy +/- 4 additional doses of PEG-ASNase. SR-Average (SRA) pts were randomized (2x2) to standard therapy +/- an intensive consolidation (IC) +/- an augmented interim maintenance/delayed intensification (AIM/ADI). SR-High (SRH) pts all received IC and two AIM/ADI phases. After 6/08, alternate week DEX (AWD, days 1-7/15-21) replaced continuous DEX (days 1-21) during DI, and escalating-dose MTX replaced oral MTX during IM. All pts received DEX days 1-28 during induction and 5-day pulses every 4 weeks during maintenance. Results: Overall ON cumulative incidence (CI) at 5y was 2.7% (133/5261), correlating with sex (F 3.7%, M 1.9%, p&lt;0.0001), age (1-2y 0.8%, 3-4y 2.0%, 5-6y 3.3%, 7-9y 7.8%, p&lt;0.0001), and risk group (SRL 2.6%, SRA 2.9%, SRH 5.7%, p=0.0009). Before 6/08, ON CI was higher for SRA pts given intensive vs standard consolidation (5.8% vs 1.9%, p=0.002), and trended higher for SRL pts given additional PEG-ASNase (4.0 vs 2.3%, p=0.09). Use of AWD significantly reduced ON CI at 3y among SRH pts (7.4% vs 1.5%, p=0.003) and further reduced ON events in SRL/SRA pts. Conclusions: Young children receiving intensified therapy for SR-ALL therapy are at risk for ON. Extended exposure to PEG-ASNase is a likely contributing factor, possibly by potentiating DEX exposure during DI. ON risk can be significantly reduced by using AWD during DI, which is now COG standard of care. Clinical trial information: NCT00103285.

Estimated long-term outcomes in children newly diagnosed with standard risk acute lymphoblastic leukemia (ALL) based on similarly treated members of the childhood cancer survivor study (CCSS) cohort.

10032 Background: Therapy for ALL has evolved such that the risk for late effects in children treated in early eras is likely different from those that will occur in children treated today. In order to estimate future risks for late effects in newly diagnosed children with standard risk ALL, we examined the long-term outcomes in a cohort of patients enrolled in the CCSS who were treated in a manner analogous to contemporary ALL therapies. Methods: We assessed outcomes that occurred ≥5 years from diagnosis in survivors of ALL enrolled in the CCSS who were aged 1-9.9 years at diagnosis, treated with 0-120 mg/m2 of anthracyclines and 0-1000 mg/m2 of alkylating agents, and no radiotherapy. We compared their risks for death, second malignant neoplasms (SMN), chronic physical health conditions and decreased health status with the general population (death and SMN) and the CCSS sibling cohort (remaining outcomes). Results: 556 survivors were eligible. At last assessment, they were a median of 27.8 years old (range 9.1 to 45.7) and 23.4 years (range 5.0-38.0) from diagnosis. 29/556 (5.2%) died (standardized mortality ratio 3.6, 95% CI 2.4-5.2); 12 of these deaths were due to ALL recurrence. Compared to siblings, the rate ratio for ≥1 chronic condition was 1.4 (95% CI 1.3-1.6), and for a severe/life threatening chronic condition was 1.7 (95% CI 1.3-2.3). Four survivors (0.7%) developed a SMN (standardized incidence ratio 1.7, 95% CI 0.5-4.5), 114 were obese (odds ratio (OR) 1.2, 95% CI 1.0-1.5), and 2 (0.4%) reported a stroke. No survivors reported symptomatic congestive heart failure. The OR for reporting adverse general health was 1.2 (95% CI 0.8-1.8), poor mental health 1.3 (95% CI 1.0-1.8), decreased functional status 2.1 (95% CI 1.4-3.0), and activity limitations 1.4 (95% CI 1.1-1.8). Conclusions: Children treated for standard risk ALL on contemporary protocols are at increased risk for future chronic health conditions and decreased health status. Despite excellent survival after leukemia therapy, such survivors will likely benefit from life-long medical care focused on the long-term risks stemming from their therapy.

Assessment of executive function (EF) among pediatric survivors of acute lymphoblastic leukemia (ALL).

9584 Background: Childhood ALL survivors are at increased risk of impaired EF. Both parent ratings and performance-based measures are used to identify vulnerable patients. We seek to assess the association between these modalities to 1) each other, and 2) need for special education and stimulants. Methods: This 22-site cross-sectional study included 256 children in remission for standard-risk precursor-B ALL previously enrolled on legacy Children's Oncology Protocols from 1993 - 2000. Patients had no history of CNS leukemia, cranial radiation, or pre-existing neurodevelopmental disorders; were ≥1 year off-therapy; and were 6-16 years at evaluation. Patients were administered performance-based measures of working memory, Digit Span (DS) and Letter-Number Sequencing (LNS) comprising the Working Memory Index (WMI) from the Wechsler Intelligence Scales for Children - Fourth Edition. Patients completed the Controlled Oral Word Association Test (COWAT). Parents completed demographic surveys and a Likert-scale assessment of executive processes, Behavior Rating Inventory of Executive Function (BRIEF). Results: There were modest correlations between BRIEF-WM scale and WMI (r=-0.20, p&lt;0.01) and subscales, DS (r=-0.17, p&lt;0.01) and LNS (r=-0.19, p&lt;0.01). BRIEF-Initiate and COWAT (r=-0.22, p&lt;0.01) were correlated. However, impaired classification based on performance-based measures was a poor predictor of parent assessment classification. The WMI and BRIEF-WM independently predicted receipt of special education (p=0.0017 and 0.0003). The BRIEF-WM and Initiate scales predicted stimulant medication use (p&lt;0.0001 and p=0.0037); however, performance-based measures did not. Conclusions: Rater and performance-based measures provide related, but different information about EF indicating the need for both. Both measurement modalities capture educational difficulties; however, only parent ratings are associated with stimulants. This may reflect the medication's success in modifying cognition in controlled environments and the BRIEF's sensitivity to the child's ability to execute tasks in the real-world setting.

Magnetic resonance imaging of the brain in survivors of childhood acute lymphoblastic leukemia

The issue of delayed neurological damage as a result of treatment is becoming increasingly important now that an increased number of children survive treatment for acute lymphoblastic leukemia (ALL). Following modification of the treatment protocols, severe symptomatic late effects are rare, and most adverse effects are detected by sensitive imaging methods such as magnetic resonance imaging (MRI) or by neuropsychological testing. In this study we aimed to determine the prevalence and characteristics of late central nervous system (CNS) damage by MRI and clinical examination in children treated for ALL. A cross-sectional study was carried out at the pediatric oncology unit of Zagazig University, Egypt, and included 25 patients who were consecutively enrolled and treated according to the modified Children’s Cancer Group (CCG) 1991 protocol for standard risk ALL and the modified CCG 1961 protocol for high-risk ALL and who had survived more than 5 years from the diagnosis. All relevant data were collected from patients’ medical records; particularly the data concerning the initial clinical presentation and initial brain imaging. All patients were subjected to thorough history and full physical examination with special emphasis on the neurological system. MRI of the brain was performed for all patients. The mean age of patients was 6.9±3.04 years at diagnosis and was 12.9±3.2 years at the time of study. The patients comprised 14 boys and 11 girls. Abnormal MRI findings were detected in six patients (24%). They were in the form of leukoencephalopathy in two patients (8%), brain atrophy in two patients (8%), old infarct in one patient (4%) and old hemorrhage in one patient (4%). The number of abnormal MRI findings was significantly higher in high-risk patients, patients who had CNS manifestations at diagnosis and patients who had received cranial irradiation. We concluded that cranial irradiation is associated with higher incidence of MRI changes in children treated for ALL. Limitation of cranial irradiation to selected patients contributed to a lower incidence of neurological complications in our study. MRI is a sensitive radiological tool to detect structural changes in children treated for ALL, even in asymptomatic cases.

CD20 has no prognostic significance in children with precursor B-cell acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children. Survival outcomes have greatly improved with combination chemotherapy and the intensification of treatment.1 Recent improvements in ALL management have largely been due to optimizing treatment according to various risk stratification schema and evaluation of minimal residual disease (MRD) at the end of induction treatment has proved valuable.2 However, up to half of relapse events occur in patients who are MRD negative at end-induction.3 We read with interest the article by Mannelli et al.4 and examined whether CD 20 was an adverse prognostic marker in children with precursor B-ALL. We carried out a retrospective analysis of children (aged 1–18 years) diagnosed with precursor B-ALL over six years between 1st January 2004 to 31st December 2009. The study was approved by the local institutional review board. We considered 20% to be the threshold for positivity (CD20+). Standard risk patients were treated with either POG 9904, POG 9905 or AALL0331, and high-risk patients were treated with either POG 9906 or AALL0232. MRD analysis was made using flow cytometry. MRD values of more than 0.1% were considered positive. Data were analyzed using SPSS software version 11.5. Survival outcomes were assessed by the Kaplan-Meier method and log rank test.5 Data analysis was censored on 31st December 2010. A total of 326 children were diagnosed with ALL over the 6-year period including 259 children treated for precursor B-ALL. Patients’ characteristics are shown in Table 1. Mean age of the study cohort was 5.2±4.0 years and median presenting WBC count was 9.1×109/L (1–841×109/L). Six patients had end of induction MRD between 0.1 to 1% and 2 had more than 1%. Fourteen patients had an event (13 relapses, 4 deaths). Mean follow up was 41 months ±20 months (median 41 months). There were 2 deaths in each of the CD 20 positive and negative groups. Table 1. Patients’ characteristics. Overall survival was 98% and this was similar in both groups. Event free survival (EFS) of the standard and the high-risk groups according to CD 20 status is shown in Figure 1A–C. Altogether, CD 20 did not indiate poor prognosis in this population. Results were similar when children with positive CD 20 were divided into those with more than 20% or those with more than 40% positivity. MRD at Day 29 was the strongest predictor of both death (P=0.00) and relapse (P=0.034). Figure 1D shows event free survival in the MRD negative group according to CD 20 status. Figure 1. (A) Event free survival in all children according to CD 20 status. (B) Event free survival in standard risk group according to CD20 status. (C) Event free survival in high-risk group according to CD20 status. (D) Event free survival in minimal residual ... Half of the children in our study group were positive for CD 20. MRD at Day 29 was able to predict outcomes in our patient cohort in agreement with previous reports.3 We did not notice any effect of CD 20 on event free survival of either standard risk ALL or high-risk ALL. CD 20 positivity did not differentiate EFS among MRD negative patients in our study. Pediatric ALL has a good outcome with modern day combination chemotherapy regimens. Our study is limited by a very small number of events in these patients. Also, MRD was positive in only 8 of 139 patients. Despite these limitations, and similar to the report by Mannelli et al.,4 we conclude that CD 20 has no prognostic significance in children with precursor B-ALL and MRD remains the most powerful predictor of outcome.

Myocardial performance index and biochemical markers for early detection of doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukaemia

Despite significant improvements in the prognosis of childhood acute lymphoblastic leukaemia (ALL), the risk of anthracycline-induced cardiovascular disease remains a major concern. This study was designed to investigate the role of the myocardial performance index (MPI) and serum concentrations of biomarkers (cTnT and NT-pro-BNP) in the early detection of subclinical anthracycline-induced functional alterations in children with ALL. All children consecutively admitted to our Pediatric Oncologic Department from January 2009 to October 2010 with a diagnosis of ALL were enrolled in this study. cTnT and NT-pro-BNP were evaluated in all patients at diagnosis, before doxorubicin therapy and 2 and 24 h following each anthracycline administration. ECG and echocardiography were performed at diagnosis and 24 h after each anthracycline course. Nineteen children with standard-risk ALL were evaluated. The mean age was 6 years. The cumulative doxorubicin dosage was 240 mg/m(2) according to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) ALL 2000 protocol. None of the 19 patients developed congestive heart failure. With increasing cumulative dosages of anthracyclines a significant increase was observed in MPI. This increase was statistically significant starting from the cumulative dosage of 120 mg/m(2) compared to baseline, while the median NT-pro-BNP level did not change significantly during treatment and cTnT levels never exceeded the cut-off value for cardiac injury. MPI value is a sensitive and accurate parameter, allowing subclinical cardiac dysfunction to be detected in children receiving anthracyclines. Lifelong cardiac surveillance of these patients is warranted in order to determine the clinical implications of increased MPI on long-term cardiac status.

Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster-ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10(-3) at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10(-4) at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

Trends in body mass index (BMI) during and after treatment for standard risk (SR) acute lymphoblastic leukemia (ALL): A report from the Children’s Oncology Group (COG).

9546 Background: Obesity is a potential complication in children treated for ALL. Limited data exist regarding timing of BMI changes and risk in long-term survivors of ALL treated without cranial radiation (CRT). This study describes temporal trends in BMI during and after therapy for SR-ALL and identifies associated factors. Methods: We conducted a retrospective cohort study of children with SR-ALL enrolled on two sequential clinical trials between 1993 and 2000 and on the COG ALTE02C2 follow-up study. Therapy included prednisone or dexamethasone during induction, the same steroid in maintenance phases, and no CRT. Standing height and weight was ascertained at diagnosis (dx), start of consolidation, start of maintenance, start of the last cycle of maintenance, and at least one year off therapy. Age and gender-specific BMI percentiles (BMI%) were calculated using 2000 CDC growth charts for patients 2-20 years. Results: The 269 subjects were a median of 3.5 years at dx, 46.7% female, 82.3% white, and a median of 9.1 years since dx at the last timepoint. The BMI% was associated with elapsed time since dx: BMI% increased between dx and consolidation (50.9%-68.3%, p &lt; 0.0001), remained stably elevated until the end of maintenance, and then decreased somewhat from the end of maintenance to the last timepoint (74.1%-70.6%, p = 0.03). After therapy, 18.1% of survivors were overweight (BMI% 85-95) and 20.9% were obese (BMI% ≥ 95). By unadjusted linear regression, higher dx BMI% was positively associated with BMI% post-therapy (p &lt; 0.0001). There was an interaction with steroid and dx BMI% such that the association between dx BMI% and post therapy BMI% was significantly greater for the dexamethasone group than the prednisone group (p = 0.01). There was no association with age at dx, gender, or race. Conclusions: In this retrospective study of SR-ALL survivors treated without CRT, we found that BMI% increased significantly in the month after dx and remained substantially elevated even several years after the end of therapy. Dx BMI% was highly associated with off-therapy BMI%, particularly in patients who had received dexamethasone rather than prednisone.

Experience with high dose methotrexate therapy in childhood acute lymphoblastic leukemia in a tertiary care cancer centre of a developing country

Intensification of systemic chemotherapy with inclusion of high dose methotrexate (HDMTX) has helped omit cranial irradiation from standard risk acute lymphoblastic leukemia (ALL) protocols, thereby eliminating the adverse side effects associated with its use. Administration of HDMTX needs meticulous monitoring. Limitations in the availability of trained staff and adequate infrastructure often pose problems in the developing world. The aim of this study was (1) to treat childhood ALL with a protocol that would have reduced use of cranial irradiation and containing infusions of high-dose methotrexate HDMTX (5 g/m(2)) without compromising on survival, and (2) evaluate the experience with HDMTX in a tertiary care cancer centre in a developing country. A retrospective chart review was done of 41 consecutive children with a confirmed diagnosis of ALL who had received at least one cycle of HDMTX as part of their consolidation treatment with regard to the patient demographic profile, details of HDMTX infusion and leucovorin rescue, toxicity, additional hospitalization, delay in next cycle of chemotherapy and survival. The clinically most significant toxicities observed were mucositis 39% (58/149) and fever 28% (42/149) together leading to additional hospital stay in 7% (11/149) cycles and neutropenia grade 3 or more in 24.8% (34/137) contributing to delay in next cycle of chemotherapy in 15% (23/149) cycles. With this strategy, it was possible to omit or reduce the dose of cranial irradiation while maintaining survival outcomes. The administration of HDMTX therapy was found to be feasible and safe with the precautions described.

A Pilot Study Investigating the Relationship Between Diet and Oxidative Stress in Infants Receiving Therapy for Acute Leukemia

Abstract 4228Pediatric leukemia patients undergoing treatment are often malnourished due to nausea, food aversions, and mucositis. Clinical observations suggest that poor nutrition worsens outcomes for this patient population. Oxidative stress may be a key intermediary linking nutrition and clinical outcomes. Previous reports suggest that diet may modulate the balance of cellular pro- and antioxidants and that oxidative stress may influence the efficacy of cancer treatment. Taken together, these data suggest that dietary changes might modulate oxidative stress and consequently impact the efficacy of therapies used to treat children with cancer.We hypothesize that age-appropriate nutrition may augment oxidative stress induced by chemotherapy and improve patient response to therapy. To address this hypothesis, we commenced a pilot study evaluating the interrelationship between nutrition and oxidative stress in children who are receiving therapy for leukemia. Twenty-four hour dietary recalls were completed and analyzed using the Minnesota Nutrition Data System for Research (NDSR) dietary analysis program to ascertain nutritional information, including caloric intake and dietary antioxidant consumption. Accordingly, the levels of pro- and anti-oxidants in mononuclear cells isolated from peripheral blood were quantified to measure oxidative stress. Levels of the reactive oxygen species (ROS) superoxide and hydrogen peroxide were measured with dihydroethidium (HE) and 2′,7′-dichlorofluorescin diacetate (DCF-DA) staining, respectively. As oxidative stress results from an imbalance of pro- and anti-oxidants, the quantity of the most common cellular antioxidant glutathione (GSH) was also measured by monochlorobimane staining.Assessments of nutrition and oxidative stress were completed for each patient at regularly scheduled intervals over a six month period. The first assessment occurred either before the patient received chemotherapy or during a prolonged break from chemotherapy whereas later assessments were conducted one month, two months, and six months after the patient began or resumed chemotherapy. Consequently, changes in nutrition and oxidative stress were monitored in response to treatment.To date, analyses have been completed for 12 patients. The median age of our patient population at the time of enrollment is 28.5 months. The oldest patient was 53 months at the time of enrollment and the youngest patient was 22 months. Seven patients are male and 6 are female. All subjects are receiving therapy for acute lymphoblastic leukemia (ALL); 7 have been diagnosed with standard risk ALL and 6 have been diagnosed with high risk ALL.Preliminary results show that ROS were increased in mononuclear cells isolated from the majority of subjects during the course of their treatment. An increase was defined as a two-fold or greater elevation in ROS at any subsequent visit compared to the baseline visit. An increase in superoxides was detected in 72.7% of patients (8 of 11). Also, an increase in hydrogen peroxide was detected in 50% of patients (6 of 12). Interestingly, the antioxidant GSH was decreased in mononuclear cells isolated from many of our patients during the course of their treatment. A decrease was defined as a drop in the quantity of GSH at all subsequent visits compared to the baseline visit. A decrease in GSH was seen in 50% of patients (6 of 12) and 33% (4 of 12) demonstrated a decrease in GSH coincident with an increase in both superoxides and hydrogen peroxide. This increase in ROS and decrease in GSH suggests that the majority of our patients experience oxidative stress during therapy.To investigate the impact of diet on oxidant status, NDSR software was used to compare the consumption of dietary antioxidants, such as vitamins A, B3, C, and E, selenium, and glutamic acid, to the corresponding amounts of ROS from the same visit. The strongest correlation was between vitamin C consumption and hydrogen peroxide levels. An inverse relationship between vitamin C consumption and hydrogen peroxide levels was apparent in 58.3% of patients (7 of 12). Though this data is preliminary, our hope is that the findings from this pilot study will begin to illuminate the relationship between diet and oxidative stress in pediatric leukemia patients and justify future work which will aid in devising dietary interventions that will modulate oxidant status to favor improved survival of children with leukemia. Disclosures:No relevant conflicts of interest to declare.