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Background Pegaspargase (PEG‐ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG‐ASP‐associated hepatotoxicity. Methods We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. Results Fifty‐two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG‐ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event‐free survival. Conclusions This real‐world data on levocarnitine supplementation during ALL induction highlights the risk of PEG‐ASP‐associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings., Patients who are adolescents or young adults and/or who are obese are at higher risk for pegaspargase‐induced hepatotoxicity. Levocarnitine supplementation may reduce the risk for hepatoxicity during induction therapy for acute lymphoblastic leukemia.

Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement.

Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children’s Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged

PURPOSE To identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide. PATIENTS AND METHODS From 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22. RESULTS Complete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; P = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC v 52.4% [44.0% to 62.4%] for HD-ADE, P = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC v 64.6% [56.2% to 74.2%] for HD-ADE, P = .1) did not differ significantly across the two arms. CONCLUSION Our findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.

The treatment of acute lymphoblastic leukemia (ALL) is one of the success stories of pediatric oncology, but challenges and questions remain, including the optimal approach to the treatment of central nervous system (CNS) leukemia. It is unclear why some children with ALL develop CNS leukemia and others do not, and there remains debate regarding optimal regimens for prophylaxis, upfront treatment, and the treatment of CNS relapses. These topics are especially important since both cranial radiation therapy (CRT) and intensive intrathecal therapy carry risks of both short- and long-term adverse effects. In this review, we aim to identify areas of ongoing debate on this topic, review the biology of CNS leukemia, and summarize clinical trial data that address some of these questions.Both retrospective and meta-analyses have demonstrated that few patients with ALL benefit from CRT as a component of CNS-directed treatment for de novo disease, allowing cooperative groups to greatly limit the number of patients undergoing CRT as part of their initial ALL regimens. More recent efforts are focusing on how best to assay for low levels of CNS disease at the time of diagnosis, as well as the biological drivers that may result in CNS leukemia in certain patients. Progress remains to be made in the identification and treatment of CNS leukemia in pediatric ALL. Advancements have occurred to limit the number of children undergoing CRT, but much has yet to be learned to better understand the biology of and risk factors for CNS leukemia, and novel approaches are required to approach CNS relapse of ALL.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. Significance: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations. See related commentary by Bornhauser and Bourquin, p. 1322. This article is highlighted in the In This Issue feature, p. 1307

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.

Although many children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) are cured with modern, risk-adapted chemotherapy regimens, 10% to 15% of patients will experience relapse or have refractory disease. Recent efforts to further intensify cytotoxic chemotherapy regimens in the frontline setting have failed as a result of excessive toxicity or lack of improvement in efficacy. As a result, novel approaches will be required to achieve cures in more newly diagnosed patients. Multiple immune-based therapies have demonstrated considerable efficacy in the setting of relapsed or refractory (R/R) disease, including CD19 targeting with blinatumomab and tisagenlecleucel and CD22 targeting with inotuzumab ozogamicin. These agents are now under investigation by the Children’s Oncology Group (COG) in clinical trials for newly diagnosed B-ALL, with integration into standard chemotherapy regimens based on clinically and biology-based risk stratification as well as disease response.

Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9–24 years) with ALL who developed Grade 3–4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase-associated hepatic toxicity and the potential role of levocarnitine in management is warranted.

Summary Background Treatment outcomes among survivors of cancer diagnosed during adolescence and early young adulthood have not been characterised independently of survivors of cancers diagnosed during childhood. We aimed to describe chronic health conditions and all-cause and cause-specific mortality among survivors of early-adolescent and young adult cancer. Methods The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study with longitudinal follow-up of 5-year survivors diagnosed with cancer before the age of 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999. We evaluated outcomes among survivors of early-adolescent and young adult cancer (aged 15–20 years at diagnosis) and survivors diagnosed at age younger than 15 years (matched on primary cancer diagnosis, including leukaemia, lymphoma, CNS tumours, neuroblastoma, Wilms tumour, soft-tissue sarcomas, and bone cancer) by comparing both groups to siblings of the same age. Mortality was ascertained with the National Death Index. Chronic health conditions were classified with the Common Terminology Criteria for Adverse Events. Standardised mortality ratios (SMRs) were estimated with age-specific, sex-specific, and calendar year-specific US rates. Cox proportional hazard models estimated hazard ratios (HRs) for chronic health conditions and 95% CIs. Findings Among 5804 early-adolescent and young adult survivors (median age 42 years, IQR 34–50) the SMR compared to the general population for all-cause mortality was 5·9 (95% CI 5·5–6·2) and among 5804 childhood cancer survivors (median age 34 years; 27–42), it was 6·2 (5·8–6·6). Early-adolescent and young adult survivors had lower SMRs for death from health-related causes (ie, conditions that exclude recurrence or progression of the primary cancer and external causes, but include the late effects of cancer therapy) than did childhood cancer survivors (SMR 4·8 [95% CI 4·4–5·1] vs 6·8 [6·2–7·4]), which was primarily evident more than 20 years after cancer diagnosis. Early-adolescent and young adult cancer survivors and childhood cancer survivors were both at greater risk of developing severe and disabling, life-threatening, or fatal (grade 3–5) health conditions than siblings of the same age (HR 4·2 [95% CI 3·7–4·8] for early adolescent and young adult cancer survivors and 5·6 [4·9–6·3] for childhood cancer survivors), and at increased risk of developing grade 3–5 cardiac (4·3 [3·5–5·4] and 5·6 [4·5–7·1]), endocrine (3·9 [2·9–5·1] and 6·4 [5·1–8·0]), and musculoskeletal conditions (6·5 [3·9–11·1] and 8·0 [4·6–14·0]) when compared with siblings of the same age, although all these risks were lower for early-adolescent and young adult survivors than for childhood cancer survivors. Interpretation Early-adolescent and young adult cancer survivors had higher risks of mortality and severe and life threatening chronic health conditions than the general population. However, early-adolescent and young adult cancer survivors had lower non-recurrent, health-related SMRs and relative risks of developing grade 3–5 chronic health conditions than childhood cancer survivors, by comparison with siblings of the same age, which were most notable more than 20 years after their original cancer. These results highlight the need for long-term screening of both childhood and early-adolescent and young adult cancer survivors. Funding National Cancer Institute and American Lebanese-Syrian Associated Charities.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a molecular subtype of high-risk B-cell ALL characterized by formation of abnormal gene fusions involving tyrosine kinase (TK) and cytokine receptor genes and activation of TK signaling. Because of the diversity of associated genetic changes, the detection of Ph-like ALL cases currently requires multiple cytogenetic and molecular assays; thus, our goal was to develop a consolidated workflow for detecting genetic abnormalities in Ph-like ALL. We found that total and targeted RNA sequencing (RNAseq)-based approach allowed the detection of abnormal fusion transcripts (EBF1-PDGFRB, P2RY8-CRLF2, RCSD1-ABL1, and RCSD1-ABL2). The bioinformatics algorithm accurately detected the fusion transcripts without prior input about possible events. Additionally, we showed that RNAseq analysis enabled evaluation for disease-associated sequence variants in expressed transcripts. While total RNAseq can be a second tier approach allowing discovery of novel genetic alterations, the targeted RNAseq workflow offers a clinically applicable method for the detection of fusion transcripts.

Purpose Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children’s Oncology Group (COG) trials to evaluate the impact of HSCT on outcome. Patients and Methods Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort. Results Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes. Conclusion Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.

Advances in health-related quality-of-life (HRQL) measurement enable point-of-care assessments. We incorporated the Patient-Reported Outcomes Measurement Information System (PROMISAYAs (18-39 years old) completed the 10-question PROMIS Global. Summary subscale scores for Global Physical Health (GPH) and Global Mental Health (GMH) were produced using established scoring algorithms (standardized mean = 50, standard deviation = 10). In addition to comparisons by treatment status, associations between lower subscale scores (45, previously defined as clinically meaningful) and patient characteristics were assessed using two-sample t-tests among those off treatment.Of 147 patients approached, 142 consented. Mean age was 24.6 ± 5.3 years; 53.5% were male; and 61.3% had hematologic malignancies. Most (76%) were off treatment; 43.0% had treatment complications. While mean GPH and GMH scores did not differ from the standardized population mean (GPH, 49.7 ± 8.8, p = 0.73; GMH, 50.5 ± 9.3, p = 0.55), mean GPH scores were lower among those on treatment (44.3 ± 9.0) than off treatment (51.5 ± 8.1, p 0.0001). There was no difference in GMH scores by treatment status. Among those off treatment, 26.9% of GPH and 22.2% of GMH scores were45. The only factor associated with lower GPH scores was treatment complications; no factors were associated with lower GMH scores.Point-of-care HRQL assessment with AYAs is feasible. Among patients off treatment, GPH scores were lower for patients with treatment complications. Further research is needed to understand factors associated with lower GMH scores in this AYA oncology population.

There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL).Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study.Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P.001) and B symptoms (63% vs 27%; P.001), and fewer had bulk disease (33% vs 77%; P.001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study.Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2018;124:136-44. © 2017 American Cancer Society.

Compared to younger and older age groups, the incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) has increased more in the adolescent and young adult (AYA) population, the cause of which is unknown. As of the last decade, only half of the AYA patients with these diseases were surviving 10 years. Strong evidence exists that favors "pediatric" treatment regimens for AYAs compared to "adult" treatment regimens in terms of survival rates, hospitalization time, toxicities, late effects, and quality of life both during and after treatment. Targeted agents are clinically accessible for certain subsets of patients with Philadelphia-like ALL, the incidence of which peaks in AYAs. Treatment teams must appreciate the complex psychosocial underpinnings in these patients in order to maximize compliance with the prolonged and complex treatment plans during the AYA years.

Intravenous immunoglobulin (IVIG) is pooled immunoglobulin G derived from human blood donors. It was introduced in the early 1980s to treat immunodeficiency disorders. Since then, its use has expanded to other fields such as neurology, rheumatology, and hematology. IVIG has been used to provide passive immunity in qualitative and quantitative immunoglobulin disorders, to neutralize antibodies in immune-mediated diseases, and as an immune modulatory agent. The difficulty of producing IVIG in high quantities, in addition to a growing list of “off-label” indications, has resulted in a worldwide shortage and increase in cost. From a pediatric hematology perspective, IVIG is considered an appropriate therapeutic option in autoimmune cytopenias, sometimes coadministrated with steroids. Its use in other hematologic disorders is questionable, and there is not sufficient evidence to recommend it. This article provides clear information to the general pediatrician about indications for IVIG therapy in children with hematologic disorders. [ Pediatr Ann . 2017;46(1):e13–e18.]

Acute lymphoblastic leukemia (ALL) is the most common and one of the most curable malignancies in children; however, it presents unique challenges in adolescents and young adults (AYAs). The purpose of this review is to discuss factors that contribute to the outcome disparities in AYAs with ALL as well as approaches that can be taken to optimize the care of this patient population.AYAs with ALL are unique and have outcomes that have lagged behind those observed in children with ALL. Contributing factors to the challenges faced by this group include distinctive disease biology, different drug pharmacology and toxicity profiles, and complex psychosocial and socioeconomic factors. Several clinical trials conducted worldwide have demonstrated that treatment with pediatric protocols significantly improves outcomes in the AYA population.Initiatives to improve outcomes for AYAs with ALL include treatment with pediatric regimens tailored to be delivered without excessive toxicity and in centers with the necessary supportive care and medical services to address the specific needs of this population. As more is understood about the unique disease biology of AYA ALL, targeted therapeutic approaches may offer promise for the future.

The diagnosis of acute lymphoblastic leukemia (ALL) is made by evaluating morphology and immunophenotype. However, appropriate risk stratification and decisions regarding the intensity of therapy are influenced by additional clinical and laboratory testing that reflect the biology of the disease. Recent years have seen tremendous progress in uncovering genetic lesions that influence the biology of ALL. In recognition of these advances, the 2008 WHO classification incorporated the category of B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities into the classification of precursor lymphoid neoplasms. Based on the knowledge available at the time, genetic lesions associated with distinct clinical features, immunophenotype, prognosis, or other unique biological characteristics were included in this category. Not surprisingly, significant novel genetic lesions that profoundly affect the biology of ALL have since been identified and will have a major impact on risk stratification and may ultimately be incorporated into future classification schemes. After establishing an initial diagnosis and treatment regimen, hematopathologists must also evaluate for minimal residual disease (MRD) to determine the need for additional intervention because MRD remains the most useful clinical indicator of disease progression and response to treatment. Doing so requires familiarity with not only morphology, but also flow cytometry and molecular genetics. Although not all of these applications are handled directly by the hematopathologist, it is our strong belief that meaningful involvement in patient care dictates that hematopathologists appreciate all aspects of ALL diagnosis and disease monitoring. This review covers the salient aspects of recent advances in the biology of ALL and evaluation of MRD, placing emphasis on how this information may ultimately be used to improve risk stratification and, as a result, patient outcomes.

Glucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL), but usage differs between cooperative group protocols. All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone. Issues to consider in the choice of induction steroid include impact on event-free and overall survival, acute morbidity such as infection risk, diabetes, and behavioural disturbances and long-term complications such as avascular necrosis. It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase, but dosing schedules (intermittent versus continuous) vary. There is no consensus on the potential benefit of steroid administration during maintenance therapy. This review will summarize the current available data on steroid use in paediatric ALL, highlighting outcomes as well as major toxicities.

The Infectious Diseases Society of America (IDSA) guidelines recommend collecting blood cultures for the first 3 days of febrile neutropenia (FN) in the clinically stable oncology patient with persistent fevers. Nonetheless, many physicians send daily blood cultures beyond 3 days, and the impact of that practice is uncertain.We reviewed pediatric FN episodes from July 2009 to May 2014 at University of Chicago Comer Children's Hospital. For each positive culture, we determined if it was a pathogen or a contaminant. We reviewed episode and patient demographics to identify risk factors for subsequent positive blood cultures in the setting of an initially negative culture.We identified 381 episodes of FN in 162 patients. Of those, 87 had a positive blood culture on day 1 (21.0% incidence of bacteremia). Of 294 episodes with a negative blood culture on day 1, six (2.04%, 95% confidence interval [CI] 0.42-3.67) had a positive culture after day 3. Of those, three were pathogens (1.02%, 95%CI -0.14 to 2.18), and only one was found in a hemodynamically stable patient (0.34%, 95%CI -0.33 to 1.01) with new mucositis. In the other two patients, Escherichia coli was isolated from blood cultures after day 10 in the setting of significant hemodynamic changes. Risk factor analysis performed in stable patients yielded nonsignificant results.Of 294 FN episodes with an initial negative blood culture, only one episode of bacteremia occurred without hemodynamic changes past day 3, supporting the IDSA guidelines to discontinue blood cultures in stable FN patients after day 3.

Adolescents and young adults (AYAs) with cancer face unique psychosocial challenges. This pilot study was aimed at describing the prevalence of psychological morbidities among AYAs with hematologic malignancies during curative-intent therapy and early survivorship and at examining provider perceptions of psychological morbidities in their AYA patients.Patients aged 15 to 39 years with acute leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma who were undergoing curative-intent therapy (on-treatment group) or were in remission within 2 years of therapy completion (early survivors) underwent a semistructured interview that incorporated measures of anxiety, depression, and posttraumatic stress (PTS). A subset of providers (n = 15) concomitantly completed a survey for each of the first 30 patients enrolled that evaluated their perception of each subject's anxiety, depression, and PTS.Sixty-one of 77 eligible AYAs participated. The median age at diagnosis was 26 years (range, 15-39 years), 64% were male, and 59% were non-Hispanic white. On-treatment demographics differed significantly from early-survivor demographics only in the median time from diagnosis to interview. Among the 61 evaluable AYAs, 23% met the criteria for anxiety, 28% met the criteria for depression, and 13% met the criteria for PTS; 46% demonstrated PTS symptomatology. Thirty-nine percent were impaired in 1 or more psychological domains. Psychological impairments were as frequent among early survivors as AYAs on treatment. Provider perceptions did not significantly correlate with patient survey results.AYAs with hematologic malignancies experience substantial psychological morbidities while they are undergoing therapy and during early survivorship, with more than one-third of the patients included in this study meeting the criteria for anxiety, depression, or traumatic stress. This psychological burden may not be accurately identified by their oncology providers.

Pediatric acute lymphoblastic leukemia is the most common childhood cancer. Although the appearance of the disease is often quite dramatic, there are many patients who present much more indolently, creating a diagnostic dilemma for the primary care pediatrician. The appropriate diagnostic work-up assesses the initial extent of disease and stability of a patient, and provides information that is important for risk stratification. Such information includes patient age and white blood cell count at diagnosis, leukemia immunophenotype, presence or absence of extramedullary disease, and blast cytogenetic abnormalities. After therapy is initiated, the response of the disease to treatment is key for predicting outcomes. Altogether, this information is used to guide overall treatment intensity. Chemotherapy is administered in sequential blocks or phases, and lasts for several years. In general, outcomes are excellent and the majority of patients survive, but there are still subsets of patients who do not fare as well, either due to resistant or recurrent disease, or due to long-term and late effects of therapy. [ Pediatr Ann . 2015;44(7):e168–e174.]

Acute lymphoblastic leukemia (ALL) affects all agegroups, although it is much more common inpediatric patients, with a peak incidence betweenthe ages of 1 and 4 years and a median age of 13 yearsat diagnosis (Surveillance, Epidemiology and EndResults [SEER] 2003–2007 data). While deregula-tion of pathways that control cell proliferation,differentiation, and survival contributes to its patho-genesis, the precise etiology of ALL is not yetunderstood. Many patients with ALL are in factchildren, and few have predisposing genetic syn-dromes or known carcinogenic exposures, such asionizing radiation or chemotherapeutic agents.Therefore increasing attention is being placed onidentifying underlying factors that increase thesusceptibility to the development of ALL. Folatemetabolism is essential to numerous cellular pro-cesses, including DNA and RNA synthesis as well asmethylation reactions involving homocysteine andDNA [1,2]. Rapidly dividing cells, therefore, havehigh folate requirements, and polymorphisms infolate-related genes can alter the amount or distribu-tion of this substrate available to cells. This has ledinvestigators to examine possible associations be-tween polymorphisms in the wide variety of genesinvolved in folate metabolism and the developmentof ALL. While there is a growing body of literatureexamining such associations, the results are not allconcordant.In this issue of Leukemia and Lymphoma,Yang et al. record the results of their study evaluatingsuch associations in the Han Chinese population [3].This study reports on polymorphisms in ninedifferent folate-related genes in both adult andpediatric patients with ALL and found that in thepopulation studied, variations in RFC1 (reducedfolate carrier 1) and MTRR (methionine synthasereductase) confer an increased risk for developingadult ALL while MTHFR (methylenetetrahydrofo-late reductase) and ABCG2 (ATP-binding cassettesub-family G member 2) polymorphisms confer adecreased risk. No significant associations werefound between polymorphisms in any of the genesstudied and the risk of pediatric ALL.The most studied folate-related gene variants todate, in relation to ALL risk, are the 677C4T and1298A4C polymorphisms in MTHFR. While thereare conflicting results from various studies, severalmeta-analyses suggest a reduced risk of adult ALLwith the homozygous TT genotype but perhaps lessof a risk reduction with this genotype in pediatricpopulations [1,4,5], similar to what was observed byYang et al. in their report here [3]. There have beenseveral studies in pediatric populations, however,which identified a reduced risk of pediatric ALL withthe 677T allele [2,6]. Fewer studies are available onother genes involved in folate metabolism, and theresults in different populations vary. In general,though, studies that evaluated polymorphisms inRFC1 found a significantly increased relative risk ofALL in patients with the 80G4A variant [2,7],similar to the results reported by Yang et al. [3]. On

Arsenic trioxide (As(2)O(3)) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As(2)O(3) is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As(2)O(3) appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As(2)O(3) on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As(2)O(3) on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As(2)O(3) and possibly other heavy metal derivatives.

Arsenic trioxide (As(2)O(3)) has potent antileukemic properties in vitro and in vivo, but the mechanisms by which it generates its effects on target leukemic cells are not well understood. Understanding cellular mechanisms and pathways that are activated in leukemic cells to control the generation of As(2)O(3) responses should have important implications in the development of novel approaches using As(2)O(3) for the treatment of leukemias. In this study, we used immunoblotting and immune complex kinase assays to provide evidence that the kinases thousand-and-one amino acid kinase 2 (TAO2) and transforming growth factor-beta-activated kinase 1 (TAK1) are rapidly activated in response to treatment of acute leukemia cells with As(2)O(3). Such activation occurs after the generation of reactive oxygen species and regulates downstream engagement of the p38 mitogen-activated protein kinase. Our studies demonstrate that siRNA-mediated knockdown of TAO2 or TAK1 or pharmacological inhibition of TAK1 enhances the suppressive effects of As(2)O(3) on KT-1-derived leukemic progenitor colony formation and on primary leukemic progenitors from patients with acute myelogenous leukemia. These results indicate key negative-feedback regulatory roles for these kinases in the generation of the antileukemic effects of As(2)O(3). Thus, molecular or pharmacological targeting of these kinases may provide a novel approach to enhance the generation of arsenic-dependent antileukemic responses.

C-reactive protein (CRP) is an acute phase reactant that is a reliable marker of systemic inflammation and has been associated with increased morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in adults. In this study, we evaluated whether early elevations of CRP were associated with various complications and nonrelapse mortality following HSCT in pediatric patients. Seventy pediatric patients had CRP levels drawn at regular time points during the first week following their transplants. Patients were followed for 100 days following transplant, and transplant-related complications were documented. Patients who subsequently developed severe infections had higher median CRP values than those without severe infections (median 8.03 mg/dL versus 1.64 mg/dL, P = .0008) as did those who suffered nonrelapse mortality compared with those who did not (12.6 mg/dL versus 2.44 mg/dL, P = .02). These findings suggest that elevated CRP values may be useful as a marker of individual pediatric patients with a higher risk for treatment-related morbidity and mortality.