Therapy For Childhood Acute Lymphoblastic Leukemia Research Articles

Mycobacterium abscessus pulmonary disease presenting with spontaneous pneumomediastinum and subcutaneous emphysema in childhood acute lymphoblastic leukemia: a case report and literature review

IntroductionMycobacterium abscessus is a rapidly growing mycobacterium commonly identified in adults with underlying pulmonary diseases but is rarely observed in children. A better understanding of this pathogen in children is essential.Case presentationWe report the case of a 49-month-old female child without previous underlying pulmonary diseases but with acute lymphoblastic leukemia (ALL). The patient was complicated with pneumonia during chemotherapy, which was primarily characterized by spontaneous pneumomediastinum and subcutaneous emphysema on chest computed tomography (CT). M. abscessus sequences were detected by metagenomic next-generation sequencing in bronchoalveolar lavage fluid. With mechanical ventilation, closed thoracic drainage, and anti-infective therapy for 6 months, the patient’s infection was controlled. The patient completed 2.5 years of treatment for ALL, and the drugs were discontinued. The patient currently remains in complete hematologic remission.DiscussionWe reviewed the literature on 33 children with M. abscessus pulmonary disease. These children mostly had underlying immunodeficiency. Chest CT most often showed nodular shadows, consolidation, and bronchiectasis. Spontaneous pneumomediastinum and subcutaneous emphysema were not reported as major manifestations.ConclusionSpontaneous pneumomediastinum and subcutaneous emphysema were our patient's main characteristics on chest CT, and this study enriches the knowledge regarding possible imaging changes in M. abscessus pulmonary disease in children. This case report reflects good clinical experience in maintaining the balance between chemotherapy and anti-infective therapy in childhood ALL.

Abstract 5216: The effect of polymorphisms in DAT1 and DRD4 on dietary intake during chemotherapy for childhood leukemia

Abstract Outcomes of acute lymphoblastic leukemia (ALL) are associated with both host and environmental factors. We hypothesized that there is also an interaction between them, with genetic variants influencing dietary choices. The dopamine transporter 1 (DAT1) and D4 subtype of the dopamine receptor (DRD4) genes are polymorphic, with a variable number of nucleotide repeats (VNTR) that affect dopaminergic neurotransmission, and reward circuitry for food cravings. Specifically, the 9-tandem repeats (9R) allele of DAT1 and the 7-tandem repeats (7R) allele of DRD4 are risk factors for eating disorders or undereating behavior in children. The goal of this study was to determine whether these polymorphisms are associated with altered dietary intake during therapy for childhood ALL. DNA was isolated from peripheral blood mononuclear cells collected from 439 children being treated on Dana Farber Cancer Institute ALL Consortium Protocol 05-001 (NCT00400946). Target alleles in DAT1 and DRD4 were determined using PCR product length analysis. Each subject was classified as having either zero or at least one copy of the target alleles. Dietary intake was previously determined using food frequency questionnaires collected at three timepoints: time of diagnosis, end of induction, and continuation therapy. As previously published dietary composition in fat and carbohydrate differed significantly among three timepoints. There was no significant difference between those with or without the target alleles in DAT1 or DRD4 in percent from fat or percent from carbohydrate at any of the three timepoints. However, significant differences were observed when dietary intake was compared to the Dietary Reference Intake (DRI). Notably, a greater portion of male participants with DAT1 9R polymorphism had fat consumption below the DRI at the time of diagnosis. On the contrary, significantly decreased portion of females with DAT1 9R had fat consumption below the DRI during continuation therapy. When compared to normative values, a significantly increased number of children had total calorie consumption below DRI during induction therapy. The DRD4 7R polymorphism was associated with fat intake below DRI during induction therapy in males. However, neither DAT1 nor DRD4 polymorphisms were related to variation in carbohydrates consumption. In addition, a greater portion of participants that carry both DAT1 and DRD4 polymorphism exhibited a trend toward undereating behavior in fat intake compared to the controls. Our results are the first to indicate that DAT1 and DRD4 polymorphisms are associated with altered dietary intake during chemotherapy for childhood ALL. Future study will further elucidate whether this modulation is associated with changes in their body weight, BMI, glucose level, and disease relapse. Citation Format: Jing Wen, Arul Duggimpudi, Shengguo Li, Elena Ladas, Kara M. Kelly, Peter D. Cole. The effect of polymorphisms in DAT1 and DRD4 on dietary intake during chemotherapy for childhood leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5216.

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia.

This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes. Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase-polymerase chain reaction, multiplex ligation-dependent probe amplification, and RNA-sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG-ALL-2013 study enrolled patients who received MRD-directed therapy. The 5-year event-free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD-guided therapy, those with ETV6-RUNX1 fusion and high hyperdiploidy had the highest 5-year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR-ABL1 ALL. Recently identified subtypes like DUX4-rearranged, ZNF384-rearranged, MEF2D-rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high-risk or very-high-risk subtypes, the TPOG-ALL-2013 regimen did not confer significant improvements compared to TPOG-ALL-2002, and the outcomes of BCR-ABL1-like, MEF2D-rearranged, and KMT2A-rearranged ALL subtypes (in addition to those of T-cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. The TPOG-ALL-2013 study yielded outcomes superior to those of patients treated in the preceding TPOG-ALL-2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. MRD-directed therapy improved the outcomes for pediatric ALL, especially standard-risk patients. Genomic analyses and MRD might be used together for risk-directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan.

Drug-Induced Liver Injury during Consolidation Therapy in Childhood Acute Lymphoblastic Leukemia as Assessed for Causality Using the Updated RUCAM.

Purpose The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL. Methods Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Results Patients with high risk (HR) and standard risk (SR)/intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively; among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SR/IR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mg/L, albumin ≤45 g/L, and gamma-glutamyl transpeptidase (GGT) > 17 U/L). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827–0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SR/IR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable + highly probable) were detected in “100% of HD-MTX + 57% of high-dose cytarabine (HD-Ara-C),” “100% of HD-MTX + 20% of pegylated asparaginase (PEG-ASP),” and “100% of HD-Ara-C + 33.3% of PEG-ASP,” respectively. Conclusion Incidence of DILI in HR patients was significantly higher than that in SR/IR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.

Epstein Barr Virus-Associated Lymphoproliferative Disorder during Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

Epstein Barr virus (EBV)-associated lymphoproliferative disorder (LPD) is a major cause of morbidity and mortality in immunodeficient patients. This disorder has been extensively described after hematopoietic stem cell (SCT) or solid organ transplant. Since the 1980's, there have been isolated case reports of pediatric patients with acute lymphoblastic leukemia (ALL), who developed EBV-LPD during ALL therapy, without undergoing SCT. Comprehensive information is unavailable regarding the prevalence, clinical manifestations, treatment, outcome and pathogenesis of such disorders in this setting.In this retrospective survey, national coordinators of International BFM (I-BFM) ALL study groups were asked to report patients ≤ 18 years of age who developed EBV-LPD during childhood ALL therapy since 2000. Patients with LPD following SCT were excluded. Complete information was requested regarding patient characteristics, leukemia and LPD characteristics, treatment and outcome. In addition, a literature search was performed, and patients described in previously published case reports were added to the series.Ten cases of EBV-LPD during childhood ALL therapy were reported by I-BFM national coordinators. Another 16 case reports were identified by a literature search, thus forming a series of 26 patients. None of the patients reported a previous history of immune deficiency or cancer in the family. Eighteen of 26 patients were male. Median age was 4.5 years (range: 2 months-16 years). Eighteen patients were diagnosed with B-ALL, 3 with T-ALL (data unavailable for 5 cases). Only 2 cases received ALL treatment according to the high-risk (HR) arm of their respective protocols. All cases were diagnosed during maintenance therapy, or 1-2 months after its cessation. The median duration of maintenance exposure until LPD diagnosis was 12.5 months (range: 3-30 months). Patients presented with a diverse and often aggressive clinical picture, with frequent extra-nodal involvement (fig. 1). Of 26 patients, 22 patients presented with fever, 12 had an infectious mononucleosis (IMN)-like prodrome days to weeks before LPD diagnosis, 13 presented with pulmonary nodules (fig. 2) and 6 had multiple intestinal perforations (fig. 3). Pathology showed a spectrum of heterogenous lesions, as defined by the World Health Organization 2008 criteria for post-transplant LPD (PTLD), including only one case with an LPD of T-cell origin. In all cases maintenance treatment was discontinued. Other treatment modalities included chemotherapy, rituximab, EBV cytotoxic T-cell lymphocytes (CTLs) and SCT (fig. 4). In 5 patients maintenance was resumed, without LPD recurrence. Three patients died of EBV-LPD, 4 had an ALL relapse, 19 experienced continued remission from both ALL and LPD.In this survey we describe the clinical manifestations, treatment and outcome of 26 patients who developed EBV-LPD during childhood ALL therapy. This is a very rare life-threatening disorder, but its exact incidence is difficult to estimate due to under-reporting, even among patients treated on clinical trials. The clinical presentation, range of pathological findings and treatment modalities were similar to PTLD. Most patients were diagnosed at a progressive stage of their disorder. Remarkably, all 26 cases were diagnosed during the maintenance phase of ALL treatment, after a median duration of 12.5 months. The majority were treated according to non-HR arms of therapy, where exposure to maintenance is usually of longer duration. There is limited information regarding immune function during maintenance therapy. EBV-LPD is a disorder resulting from proliferation of infected B-cells in the setting of deficient cytotoxic T-cell surveillance. Our findings suggest that the pathogenesis of this disorder is related to an immune dysregulation which occurs specifically under exposure to maintenance therapy, and that the B-cell and T-cell compartments may be differentially affected during this phase of therapy. These rare cases may enhance our understanding of the biology of EBV infection in immunodeficient patients. The vast majority of children with ALL do not develop EBV-LPD during maintenance therapy, suggesting a role for host genetic predisposition, which may be further investigated in future. [Display omitted] DisclosuresSchrappe:JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Medac: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Dietary Antioxidant Micronutrient Intake and Toxicity during Remission Induction in Children with Acute Lymphoblastic Leukemia (ALL): Results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 05-001

Introduction: Treatment related toxicities are a major contributor to morbidity during induction therapy in childhood ALL. Our prior study in 103 children with ALL suggested that low intakes of antioxidant micronutrients were associated with toxicity and delays in chemotherapy administration (Am J Clin Nutr 79:1029, 2004). The objective of this study was to examine whether inadequate antioxidant micronutrient dietary intake in children with ALL is associated with episodes of infection or ≥grade 3 mucositis during Remission Induction.Methods: Assessment of dietary intake was collected in patients (pts) ages 1-17.9 years enrolled on the DFCI ALL Consortium Protocol 05-001 from 2005-2011. Institutional review board approval was obtained by each of the 9 participating centers. Grade 3 or higher (NCI CTCAEvs) mucositis, culture positive bacteremia and fungemia, and radiographic invasive fungal disease were prospectively collected. Dietary intake was assessed with the Harvard Service Food Frequency Questionnaire (FFQ) for children ages 1-5 years and the Youth and Adolescent Harvard FFQ for children ages 5-18 years and queried about intake in the past 30 days at the end of induction. Dietary antioxidant intake from food sources ± supplementation was examined by comparing consumption above and below recommended intake for age and sex as per the Dietary Reference Intake (DRI). Micronutrient intake was summarized with descriptive statistics and plotted by the presence/absence of a given toxicity in induction. Categorical and continuous variables were compared between group with the Fisher's exact test and the Wilcoxon rank sum test respectively. Logistic regression was used to model the probability of a given toxicity univariately and with a multivariable adjustment for sex and age.Results: Among 794 eligible pts, 561 (71%) had analyzable FFQs. The sample with dietary surveys responses was marginally younger (p=0.06) and more often classified as initial standard risk (p=0.01) than those with no end of induction survey. DRI recommendations were not met for vitamin C (18%), vitamin E (67%) and zinc (12%); 39% of pts reported zinc overconsumption. 141 (25%) of pts with dietary data had ≥1 bacterial and/or fungal infection, 131 (23%) had ≥1 bacterial infection, and 19 (3%) had ≥1 fungal infection. 24 (4%) pts experienced at least 1 event of ≥grade 3 mucositis. Female sex was associated with overall and bacterial infection (p=0.02) and marginally with mucositis (p=0.06). The proportion of patients with ≥Grade 3 mucositis was marginally higher (p=0.06) for those not meeting the vitamin C recommendation (OR=2.3; 95% CI 1.0-5.5), but was not significant (p=0.10) in a multivariable model. Supplementation was reported by 88 (16%) for zinc, vitamins C, E, and A in combination, 16 (3%) for β-carotene and total carotene, and 87 (15%) for vitamin E alone. Intake levels of vitamins C, E, and A, zinc and total carotenoids from food sources and total (food + supplementation) were compared for pts with and without infection and mucositis (unadjusted for age/sex) (Figure 1). Bacterial infection was associated with low intake from food only of zinc (p=0.02), vitamin A (p=0.01), and vitamin E (p=0.049). Mucositis was associated with the following: low intakes of vitamin C from food (p=0.04), vitamin E from food (p=0.03), total lycopene (p=0.03), total α-carotene (p=0.01), total β-carotene (p=0.007) and from food (p=0.008), total carotene (p=0.005) and carotene from food (p=0.006), and total vitamin A (p=0.01) and vitamin A from food (p=0.004). Females age <10 had higher rates of bacterial infection with low β-carotene (p=0.05) and vitamin A from food (p=0.004). In males age ≥10, low vitamin E from food was observed in those with bacterial infections (p=0.05). Supplementation did not confer an added benefit for most nutrients.Conclusions: Confirming our pilot study, data from a large prospective cohort show that low dietary intakes of antioxidant vitamins, carotenoids and zinc primarily from food sources predict risk for bacterial infection or mucositis during induction therapy for childhood ALL. Dietary supplementation for most vitamins and minerals did not confer an added benefit for prevention of infection or mucositis over levels obtained from food. Our results suggest a possible modifiable dietary intervention to reduce toxicity during induction therapy for ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia.

As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0–17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.

Lack of Benefit of Extended Vincristine and Dexamethasone Pulses during Maintenance Treatment of Childhood Acute Lymphoblastic Leukemia: A Multicenter Randomized Controlled Study of Chinese Children Cancer Group (CCCG)-ALL-2015

Introduction: The efficacy of extended duration of vincristine (VCR) and dexamethasone (DEX) pulses in the treatment of childhood acute lymphoblastic leukemia (ALL) is uncertain in the context of contemporary chemotherapy. By contrast, the long-term sequelae of vincristine-induced peripheral neuropathy and dexamethasone-related metabolic syndrome, osteonecrosis, and neurocognitive impairment are well recognized. We therefore conducted a randomized study in the CCCG-ALL-2015 protocol participated by 20 hospitals in China to compare the event-free survival (EFS) and overall survival (OS) between children with newly diagnosed ALL who did or did not receive extended duration of VCR+DEX pulses during maintenance treatment. Methods: After remission induction and consolidation treatment with high-dose methotrexate and mercaptopurine, all patients received antimetabolite-based maintenance treatment. During the initial 20-week of maintenance treatment, low-risk (LR) patients received two reinduction cycles and three pulses of VCR+DEX pulses, while intermediate-/high-risk (I/HR) patients received daily mercaptopurine interrupted every three weeks with PEG-asparaginase, mercaptopurine, daunorubicin, and VCR+DEX pulses for 5 courses followed by a reinduction treatment. During the subsequent maintenance treatment, all patients received VCR+DEX pulses every 4 weeks for 5 cycles. All Philadelphia chromosome (Ph)-negative patients were then stratified and randomized during the fifth cycle of maintenance course (between weeks 51 and 53) to or not to receive the VCR+DEX pulse every 8 weeks for 7 cycles between weeks 54 and 109; the remaining maintenance treatment between weeks 110 and 125 consisted of only mercaptopurine and methotrexate. Results: Between January 2015 and December 2018, 3985 eligible Ph-negative patients, including 2318 (58.2%) LR patients and 1667 (41.8%) I/HR patients, were enrolled in the study. With a median follow-up of 2.53 years (IQR 1.82-3.26), the 4-year event-free survival (EFS) and overall survival (OS) rates were 91.6% (95% CI 89.4-93.9) and 98.8% (95% CI 98.2-99.4) in the LR patients, and 85.9% (95% CI 83.2-88.7) and 95.4% (95% CI 93.8-96.9) in the I/HR patients, respectively. The 4-year OS were 99.0% (95%CI, 98.3%-99.8%) in the 1145 LR patients randomized to receive VCR+DEX pulse (LR-A) and 98.6% (95% CI, 97.7%-99.5%) in the 1173 LR patients not to receive the pulse (LR-B, hazard ratio 1.5, 95% CI 0.6-4.0; p=0.374, Fig 1A). The 4-year EFS were 91.1% (95% CI, 87.4%-95.1%) in LR-A group and 92.0% (95% CI, 89.6%-94.5%) in LR-B group (hazard ratio 1.3, 95% CI 0.8-1.9; P=0.27; Figure 1B). There were no significant differences between LR-A and LR-B group among patients with or without the t (12;21) (ETV6-RUNX1) in univariate analysis (Table1). Likewise, there was no significant difference in the 4-year OS between the 834 I/HR patients who did (I/HR-A) and the 833 I/HR patients who did not (I/HR-B) receive the pulse: 94.3% (95% CI, 91.7%-97.0%) versus 96.3% (95%CI 94.6%-98.0%, hazard ratio 0.8, 95% CI 0.4-1.4; P=0.421) (Fig 1C). The 4-year EFS were 83.6% (95%CI 79.2%-88.3%) for I/HR-A group and 88.1% (95%CI 85.1%-91.2%, P=0.372) for I/HR-B group (hazard ratio 0.9, 95% CI 0.6-1.2; P=0.37) (Figure 1D). There were no significant differences between I/HR-A and I/HR-B group among patients with B-ALL, T-ALL or t (1;19) (TCF3-PBX1) in the univariate analysis (Table1). Conclusion: The additional pulses of VCR+DEX pulse beyond one year of maintenance treatment had no impact on 4-year EFS or OS among LR or I/HR patients. If this finding remains unchanged with additional follow-up, the VCR+DEX pulses can be omitted after one year of maintenance therapy in childhood ALL. Disclosures No relevant conflicts of interest to declare.

Systematic review of the effects of bisphosphonates on bone density and fracture incidence in childhood acute lymphoblastic leukaemia.

EMBASE, Medline and the Cochrane Library were thoroughly searched by two researchers. Inclusion criteria was any child under the age of 18years with a diagnosis of ALL, who had received any bisphosphonate treatment and had serial measurements of bone density performed thereafter. All primary research studies of any study design, excluding case reports, were included. Ten full text papers were identified with two exclusively meeting the inclusion criteria. Both studies administered bisphosphonates to children receiving maintenance chemotherapy for varying durations. Bone density was assessed at regular intervals by dual x-ray absorptiometry (DXA). The majority of participants had an improvement in bone density at the end of each study. However, no size adjustment of DXA data was performed. Limited information on fracture occurrence was provided by one study but did not include routine screening for vertebral fractures. This systematic review identified that there is insufficient evidence to support routine use of prophylactic bisphosphonate therapy in childhood ALL for prevention of fracture and improvement of bone mass. Future well-designed clinical trials in those at highest risk of fractures in ALL are now needed.

Expression Pattern of Long Non-coding RNA Growth Arrest-specific 5 in the Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia.

SummaryBackgroundLong non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing GAS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response.MethodsGAS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology.ResultsOur results have shown interindividual differences in GAS5 expression at all time points. For each ALL patient, GAS5 expression was higher on day 15 in comparison to its level at diagnosis (p<0.0005). On day 33, the level of GAS5 expression decreased in comparison with day 15 (p<0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per μL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009).ConclusionsOur results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.

Bovine Colostrum Against Chemotherapy-Induced Gastrointestinal Toxicity in Children With Acute Lymphoblastic Leukemia: A Randomized, Double-Blind, Placebo-Controlled Trial.

The toxic effect of chemotherapy on the gastrointestinal tract may lead to mucositis and is associated with the pathogenesis of other treatment-related complications. We hypothesized that nutrition supplementation with bovine colostrum, rich in bioactive factors, would ameliorate gastrointestinal toxicity and reduce the incidence of fever and infectious complications during induction treatment for childhood acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were included in a 2-center, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive a daily colostrum or placebo supplement during 4 weeks of induction treatment. Data on fever, bacteremia, need for antibiotics, and mucosal toxicity were prospectively collected. (Trial registration: www.clinicaltrials.gov NCT01766804). Sixty-two patients were included. No differences were found for the primary outcome (number of days with fever). No difference was observed for neutropenic fever, intravenous antibiotics, or incidence of bacteremia. Peak severity of oral mucositis was significantly reduced by colostrum (7/29 patients, 24% mild; 6/29, 21% moderate; 1/29, 3% severe) compared with placebo (12/31, 39% mild; 1/31, 3% moderate; 7/31, 23% severe) (P = 0.02). Among patients receiving at least 1 dose of supplement (colostrum: n = 22; placebo: n = 30), the peak weekly self-reported oral mucositis score was overall significantly less severe in the colostrum group (P = 0.009). The use of prophylactic bovine colostrum showed no effect on fever, infectious morbidity, or inflammatory responses. Nevertheless, these data may suggest protective effects on the oral mucosa during induction therapy in childhood ALL, encouraging additional studies confirming these findings.

Early Imaging-Based Predictive Modeling of Cognitive Performance Following Therapy for Childhood ALL

In the United States, Acute Lymphoblastic Leukemia (ALL), the most common child and adolescent malignancy, accounts for roughly 25% of childhood cancers diagnosed annually with a 5-year survival rate as high as 94% [1]. This improved survival rate comes with an increased risk for delayed neurocognitive effects in attention, working memory, and processing speed [2]. Predictive modeling and characterization of neurocognitive effects are critical to inform the family and also to identify patients for interventions targeting. Current state-of-the-art methods mainly use hypothesis-driven statistical testing methods to characterize and model such cognitive events. While these techniques have proven to be useful in understanding cognitive abilities, they are inadequate in explaining causal relationships, as well as individuality and variations. In this study, we developed multivariate data-driven models to measure the late neurocognitive effects of ALL patients using behavioral phenotypes, Diffusion Tensor Magnetic Resonance Imaging (DTI) based tractography data, morphometry statistics, tractography measures, behavioral, and demographic variables. Alongside conventional machine learning and graph mining, we adopted "Stability Selection" to select the most relevant features and choose models that are consistent over a range of parameters. The proposed approach demonstrated substantially improved accuracy (13% - 26%) over existing models and also yielded relevant features that were verified by domain experts.

Incidence and Risk Factors for Hypertension During Childhood Acute Lymphoblastic Leukemia Therapy

To determine the incidence of hypertension among children during the induction and re-induction phases of acute lymphoblastic leukemia (ALL) therapy and association with possible risk factors. A retrospective analysis of 208 consecutive pediatric (age <18 y) ALL patients, treated per BFM-95 protocol between January 2009 and December 2013. Data were analyzed to determine the incidence of hypertension and risk factors for its development. Incidence of hypertension requiring antihypertensive medication, was 29% (61/208) during induction and 17% (33/198) during re-induction (P=0.003). Median (range) age of patients developing hypertension was 4 y (4 mo to 8 y). Age <10 y and presence of constipation were independently predictive of hypertension by multivariate analysis. The present study reports a high incidence of hypertension among children undergoing ALL induction therapy.

Role of miRNAs in Treatment Response and Toxicity of Childhood Acute Lymphoblastic Leukemia

Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.

Intermittent Versus Continuous Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOHPO ALL2008 Randomized Study

Background Asparaginase is an essential drug for childhood acute lymphoblastic leukemia (ALL) and is frequently given for months to obtain continuous asparagine depletion. This causes significant toxicity. We randomized patients to continuous versus intermittent asparaginase, hypothesizing decreased toxicity with unchanged efficacy (www.clinicaltrials.gov: NCT00819351). Methods Children (median age: 4·2 years) treated for non-high risk ALL according to the NOPHO ALL2008 protocol received five intramuscular pegylated asparaginase injections (1·000 IU/m2) biweekly and were then randomized to additional three (6 weeks intervals, N=309, experimental arm) versus ten (two weeks intervals, N=316, standard arm) doses. Primary endpoint was non-inferior (6% margin) disease free survival (DFS). Toxicity reduction was secondary endpoint. Occurrence of asparaginase-associated hypersensitivity, osteonecrosis, pancreatitis and thromboembolism were prospectively registered at quarterly intervals. Findings After a median follow-up of 4·1 years, the 7-year DFS was 90·4% (95% confidence interval, 85·4-95·4) and 90·8% (95% confidence interval, 87·0-94·6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first toxicity (hypersensitivity (N=13), osteonecrosis (N=29), pancreatitis (N=24), thromboembolism (N=17)) was 9·3% in the experimental arm and 18·1% in the standard arm (P=0·001). Toxicity reduction was confirmed in sex- and risk group-adjusted Cox regression analysis stratified by age (≥10 and <10 years) (hazard ratio 0·48; P=0·001). The experimental arm had the lowest incidences for all four toxicities, reaching significance for pancreatitis (6-month risk 5·8% versus 1·3%; P=0·002). Interpretation The excellent cure rates and reduced toxicity risk support intermittent asparaginase therapy in future childhood acute lymphoblastic leukemia therapy. Trial Registration Number: www.clinicaltrials.gov: NCT00819351 Funding: The Danish Childhood Cancer Foundation and the Danish Cancer Society. Declaration of Interest: BKA is leading a sponsor initiated study financed by Erytech Pharma (www.clinicaltrials.gov: NCT03267030). All other authors declare no conflicts of interest. Ethical Approval: The protocol was approved by the National Medicines Agencies (Eudract no. 2008-003235-20), relevant ethical committees and registered at www.clinicaltrials.gov (NCT00819351).

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency. We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.

ANALYSIS OF INDUCTION PHASE GLUCOCORTICOID USE ON ADRENAL SUPPRESSION IN PEDIATRIC PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Glucocorticoids play an important role in the treatment of acute lymphoblastic leukemia (ALL). However, supraphysiological doses may cause suppression of the adrenal. Adrenal suppression resulting in reduced cortisol response may cause an inadequate host defence against infections, which remains a cause of morbidity and mortality in children with ALL. The occurrence of adrenal suppression before and after glucocorticoid therapy for childhood ALL is unclear. The aim of this study is to analysis the effect of glucocorticoid on cortisol levels during induction phase chemotherapy in children with acute lymphoblastic leukemia. A cross-sectional, observational prospective study was conducted to determine the effect of glucocorticoid on cortisol levels in children with acute lymphoblastic leukemia. Patients who met inclusion criteria were given dexamethasone or prednisone therapy for 49 days according to the 2013 Indonesian Chemotherapy ALL Protocol. Cortisol levels were measured on days 0, 14, 28, 42 and 56 of induction phase chemotherapy. There were 24 children, among 31 children recruited, who suffered from acute lymphoblastic leukemia. Before treatment, the means of cortisol levels were 228.95 ng/ml in standard risk group (prednisone) and 199.67 ng/ml in high risk group (dexamethasone). In standard risk group, the adrenal suppression occurs at about day 56. There was a significant decrement of cortisol levels in high risk group in days 14, 28, 42 against days 0 of induction phase (p=0.001). Both groups displayed different peak cortisol levels after 6 week of induction phase (p=0.028). Dexamethasone resulted in lower cortisol levels than prednisone during induction phase chemotherapy in children with acute lymphoblastic leukemia.

Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: Risk factors and management.

Cerebral sinus venous thrombosis (CSVT) is a rare but serious complication of childhood acute lymphoblastic leukemia (ALL) therapy. No available consensus exists regarding its risk factors and appropriate management due to the rarity of cases. Out of 209 ALL patients aged 1-21 years treated at the Children's Cancer Center of Lebanon between May 2002 and May 2015, 13 developed CSVT during therapy. Patient characteristics, clinical management, and outcomes were studied. The incidence of CSVT was 6.2% (95% confidence interval [CI]: 3.4-10.4). Using univariate analysis, increased risk of CSVT was observed with age >10 years (odds ratio [OR]: 3.56, 95% CI: 1.13-11.2), T-cell immunophenotype (OR: 4.14, 95% CI: 1.16-14.7), and intermediate/high risk disease (OR: 3.4, 95% CI: 1.03-11.7). The only statistically significant risk factor by multivariate analysis was the treatment as per the intermediate-/high-risk protocol (HR: 15.6, 95% CI: 1.43-171.3). Most cases (77%) occurred in the postinduction phases of treatment while receiving a combination of asparaginase and dexamethasone rather than prednisone. Treatment with low molecular weight heparin (LMWH) for a minimum of 3 months and until significant radiological improvement is observed resulted in 100% survival rate. All but one patient had complete neurological recovery. CSVT is an important complication of childhood ALL therapy. Postinduction combined asparaginase and dexamethasone intensive treatment for intermediate-/high-risk patients was the most important risk factor. Treatment with LMWH for a minimum of 3 months, and until asparginase therapy is over, with major radiological improvement seems to be effective and feasible.

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia.

High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy.

During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.