Differential Effects of JAK1 vs. JAK2 Inhibition in Mouse Models of Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in pre-clinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, the JAK2 inhibitor fedratinib and the JAK1/2 inhibitor ruxolitinib. All three drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFNg)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, where perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, while fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent pro-inflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.

Mortality Risk Factors in Pediatric Onco-Critical Care Patients and Machine Learning Derived Early Onco-Critical Care Phenotypes in a Retrospective Cohort.

OBJECTIVES: To use supervised and unsupervised statistical methodology to determine risk factors associated with mortality in critically ill pediatric oncology patients to identify patient phenotypes of interest for future prospective study. DESIGN: This retrospective cohort study included nonsurgical pediatric critical care admissions from January 2017 to December 2018. We determined the prevalence of multiple organ failure (MOF), ICU mortality, and associated factors. Consensus k-means clustering analysis was performed using 35 bedside admission variables for early, onco-critical care phenotype development. SETTING: Single critical care unit in a subspeciality pediatric hospital. INTERVENTION: None. PATIENTS: There were 364 critical care admissions in 324 patients with underlying malignancy, hematopoietic cell transplant, or immunodeficiency reviewed. MEASUREMENTS: Prevalence of multiple organ failure, ICU mortality, determination of early onco-critical care phenotypes. MAIN RESULTS: ICU mortality was 5.2% and was increased in those with MOF (18.4% MOF, 1.7% single organ failure [SOF], 0.6% no organ failure; p ≤ 0.0001). Prevalence of MOF was 23.9%. Significantly increased ICU mortality risk was associated with day 1 MOF (hazards ratio [HR] 2.27; 95% CI, 1.10-6.82; p = 0.03), MOF during ICU admission (HR 4.16; 95% CI, 1.09-15.86; p = 0.037), and with invasive mechanical ventilation requirement (IMV; HR 5.12; 95% CI, 1.31-19.94; p = 0.018). Four phenotypes were derived (PedOnc1-4). PedOnc1 and 2 represented patient groups with low mortality and SOF. PedOnc3 was enriched in patients with sepsis and MOF with mortality associated with liver and renal dysfunction. PedOnc4 had the highest frequency of ICU mortality and MOF characterized by acute respiratory failure requiring invasive mechanical ventilation at admission with neurologic dysfunction and/or severe sepsis. Notably, most of the mortality in PedOnc4 was early (i.e., within 72 hr of ICU admission). CONCLUSIONS: Mortality was lower than previously reported in critically ill pediatric oncology patients and was associated with MOF and IMV. These findings were further validated and expanded by the four derived nonsynonymous computable phenotypes. Of particular interest for future prospective validation and correlative biological study was the PedOnc4 phenotype, which was composed of patients with hypoxic respiratory failure requiring IMV with sepsis and/or neurologic dysfunction at ICU admission.

Rituximab administration in pediatric patients with newly diagnosed acute lymphoblastic leukemia.

Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1-18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P > 0.999), anti-pegaspargase antibodies (P = 0.327), or pancreatitis (P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.

Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patients without PBB (46.9% vs. 22.7%, p < 0.001). Further, absence of PBB was associated with decreased rates of leukaemia involvement of the central nervous system (p < 0.001).

Impact of High Disease Burden on Survival in Pediatric Patients with B-ALL Treated with Tisagenlecleucel.

CD19-specific chimeric antigen receptor (CAR) T-cell therapies, including the FDA-approved tisagenlecleucel, induce high rates of remission in pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, post-treatment relapse remains an issue. Optimal management of B-ALL after tisagenlecleucel treatment remains elusive, and continued tracking of outcomes is necessary to establish a standard of care for this population. We sought to evaluate outcomes on the real-world use of tisagenlecleucel in a contemporary pediatric patient population and to identify risk factors influencing event-free survival (EFS) and overall survival (OS). Additionally, we aimed to describe post-tisagenlecleucel management strategies, including use of allogeneic hematopoietic cell transplantation (AlloHCT) or repeat CAR T-cell infusions. We report on 31 pediatric and adolescent and young adult patients (AYA) with B-ALL, treated with lymphodepleting chemotherapy followed by tisagenlecleucel. Patients were treated at Johns Hopkins Hospital and St. Jude Children's Research Hospital between March 2018 and November 2020. Data on patient, disease, and treatment characteristics were collected retrospectively from medical records and described. EFS and OS were estimated by the Kaplan-Meier method and compared by the log-rank test. Single-factor and multiple-factor analysis of EFS and OS were performed by fitting Cox regression models. Of the 30 evaluable patients, 25 (83.3%) experienced a complete response, with 21 having negative minimal residual disease. Treatment was well tolerated, with expected rates of cytokine release syndrome (61.3%) and immune effector cell-associated neurotoxicity (29%). After initial complete response, 12 patients (48%) had subsequent disease recurrence, with CD19-negative relapse (n = 6) occurring sooner than CD19-positive relapse (P = .0125). With a median follow-up time of 386 days (range 11-1187 days), the EFS for the entire cohort (n = 31) at 6 and 12 months after infusion was 47% (95% confidence interval [CI], 28.4%-63.4%) and 35.2% (95% CI, 18.4%-52.5%), respectively. In multivariate analysis, high pretreatment leukemic burden (≥5% bone marrow blasts) was an independent risk factor for inferior EFS (HR 5.98 [95% CI, 1.1-32.4], P = .0380) and OS (HR 4.2 [95% CI, 1.33-13.39], P = .0148). Tisagenlecleucel induced high initial response rates in a contemporary cohort of pediatric and AYA patients with B-ALL. However, 48% of patients experienced subsequent disease relapse, including 6 with antigen-escape variants. This highlights a considerable limitation of single-agent autologous CD19-CAR T-cell therapy. Pretreatment leukemic disease burden of ≥5% blasts was significantly associated with worse outcomes in this study, including lower EFS and OS. Our findings suggest that reducing preinfusion leukemic burden is a viable treatment strategy to improve outcomes of CAR T-cell therapy.

Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19-specific CAR T-cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T-cell therapy (P-value = 0·018) and overall survival (P-value = < 0·0001).

Clinicopathologic and prognostic features of TdT-negative pediatric B-lymphoblastic leukemia.

Little is known about B-lymphoblastic leukemia (B-ALL) that lacks expression of terminal deoxynucleotidyl transferase (TdT). To address this, we performed the largest study to date of TdT-negative B-ALL using data from St. Jude Total XV and XVI clinical trials. Compared to TdT-positive B-ALL (n = 896), TdT-negative B-ALL (n = 21) was associated with younger age (median, 1.4 versus 6.8 years, P < 0.001), higher white blood cell count (median, 52.8 versus 9.9 × 109/L, P < 0.001), absence of hyperdiploidy (0 versus 27.8%, P = 0.002), KMT2A rearrangement (100 versus 1.9%, P < 0.001), and inferior 5-year event-free survival (EFS) (76.2 versus 90.3%, P = 0.047). In the context of KMT2A-rearranged B-ALL (n = 38), TdT-negativity was significantly associated with the MLLT1 rearrangement partner (P = 0.026) but was not independently predictive of survival, suggesting that the high-risk features of TdT-negative B-ALL are secondary to underlying KMT2A rearrangements. Finally, we compared the sensitivity of TdT-negativity to neuron-glial antigen 2 (NG.2) expression for the detection of KMT2A rearrangements and found that 63% of KMT2A-rearranged B-ALL cases not identified by NG.2 were TdT-negative. The results of this study expand the spectrum of immunophenotypic features that are specific for high-risk KMT2A rearrangements in pediatric B-ALL and can be readily implemented using existing standard acute leukemia flow cytometry panels.

Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase.

PURPOSE: We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL). METHODS: We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m2 IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m2 or 3500 IU/m2 IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM. RESULTS: During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3). CONCLUSIONS: The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.

Experience using intravenous posaconazole in paediatric and young adult oncology patients.

BACKGROUND: Posaconazole exhibits broad-spectrum antifungal activity. An IV formulation became available in 2014. Few studies describing the use of this formulation exist in patients under the age of 18 years. This study describes our experience using IV posaconazole in paediatric and young adult cancer patients. METHODS: This single-centre retrospective chart review evaluated patients who received IV posaconazole and had at least one posaconazole plasma concentration obtained after five or more days with a consistent dosage. Relationships between doses required to achieve a plasma concentration of ≥1 µg/mL and patient age, weight and body surface area (BSA) were evaluated. The clinical record was reviewed to identify descriptions of any adverse events. RESULTS: Twenty-five patients were analysed, with a median age of 10.5 years (range 1.9-22.9 years; 92% were <18 years). All patients were able to achieve a posaconazole plasma concentration ≥1 µg/mL during their treatment course. The daily mg/kg/day dose required to achieve the target concentration decreased significantly with increasing age of the patient (P = 0.018). Assessment of dosage based on BSA suggested a requirement of 225 mg/m2/day across all age groups <18 years. Adverse events documented in the clinical record were consistent with those described with the oral formulations. No CNS toxicities were observed with use of IV posaconazole. CONCLUSIONS: Concentrations ≥1 µg/mL are achievable and a BSA-based dosing approach may allow a consistent empirical dose for patients <18 years of age. Therapeutic drug monitoring is recommended to ensure patients achieve therapeutic concentrations.

Evaluation of Chest Radiographs of Children with Newly Diagnosed Acute Lymphoblastic Leukemia.

OBJECTIVE: To evaluate the diagnostic yield of baseline chest radiographs (CXRs) of children with acute lymphoblastic leukemia (ALL). STUDY DESIGN: We reviewed the CXR findings at diagnosis for 990 patients aged 1-18 years with ALL treated during the Total XV and XVI studies at St. Jude Children's Research Hospital and evaluated the associations of these findings with clinical characteristics and initial management. RESULTS: Common findings were peribronchial/perihilar thickening (n = 187 [19.0%]), pulmonary opacity/infiltrate (n = 159 [16.1%]), pleural effusion/thickening (n = 109 [11.1%]), mediastinal mass (n = 107 [10.9%]), and cardiomegaly (n = 68 [6.9%]). Portable CXRs provided results comparable with those obtained with 2-view films. Forty of 107 patients with a mediastinal mass (37.4%) had tracheal deviation/compression. Mediastinal mass, pleural effusion/thickening, and tracheal deviation/compression were more often associated with T-cell ALL than with B-cell ALL (P < .001 for all). Pulmonary opacity/infiltrate was associated with younger age (P = .003) and was more common in T-cell ALL than in B-cell ALL (P = .001). Peribronchial/perihilar thickening was associated with younger age (P < .001) and with positive central nervous system disease (P = .012). Patients with cardiomegaly were younger (P = .031), more often black than white (P = .007), and more often categorized as low risk than standard/high risk (P = .017). Patients with a mediastinal mass, pleural effusion/thickening, tracheal deviation/compression, or pulmonary opacity/infiltrate were more likely to receive less invasive sedation and more intensive care unit admissions and respiratory support (P ≤ .001 for all). Cardiomegaly was associated with intensive care unit admission (P = .008). No patients died of cardiorespiratory events during the initial 7 days of management. CONCLUSIONS: The CXR can detect various intrathoracic lesions and is helpful in planning initial management.

Reduced-dose intensity therapy for pediatric lymphoblastic leukemia: long-term results of the Recife RELLA05 pilot study.

Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥ 1 and < 10 years), white blood cell count of <50 ×109/L, lack of extramedullary leukemia, and minimal residual disease level of <0.01% on remission induction day 19. Except for 2 doses of daunorubicin, treatment of patients with VLR B-ALL consisted of a combination of agents with relatively low myelotoxicity profiles, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine. Cyclophosphamide, systemic cytarabine, and central nervous system radiotherapy were not used. Of 454 patients with ALL treated at the Instituto de Medicina Integral Professor Fernando Figueira in Recife, Brazil, between December 2005 and June 2015, 101 were classified as having VLR B-ALL. There were no cases of death resulting from toxicity or treatment abandonment during remission induction. At a median follow-up of 6.6 years, there were 8 major adverse events: 6 relapses, 1 treatment-related death (from septicemia) during remission, and 1 secondary myeloid leukemia. The estimated 5-year event-free and overall survival rates were 92.0% ± 3.9% and 96.0% ± 2.8%, respectively. The 5-year cumulative risk of relapse was 4.24% ± 2.0%. The treatment was well tolerated. Episodes of neutropenia were of short duration. Patients with B-ALL selected by a combination of presenting features and degree of early response can be successfully treated with a mildly myelosuppressive chemotherapy regimen.

A Multilevel Analysis of U.S. Hospital Patient Safety Culture Relationships With Perceptions of Voluntary Event Reporting.

OBJECTIVES: Patient safety events offer opportunities to improve patient care, but, unfortunately, events often go unreported. Although some barriers to event reporting can be reduced with electronic reporting systems, insight on organizational and cultural factors that influence reporting frequency may help hospitals increase reporting rates and improve patient safety. The purpose of this study was to evaluate the associations between dimensions of patient safety culture and perceived reporting practices of safety events of varying severity. METHODS: We conducted a cross-sectional survey study using previously collected data from The Agency for Healthcare Research and Quality Hospital Survey of Patient Safety Culture as predictors and outcome variables. The dataset included health-care professionals in U.S. hospitals, and data were analyzed using multilevel modeling techniques. RESULTS: Data from 223,412 individuals, 7816 work areas/units, and 967 hospitals were analyzed. Whether examining near miss, no harm, or potential for harm safety events, the dimension feedback about error accounted for the most unique predictive variance in the outcome frequency of events reported. Other significantly associated variables included organizational learning, nonpunitive response to error, and teamwork within units (all P < 0.001). As the perceived severity of the safety event increased, more culture dimensions became significantly associated with voluntary reporting. CONCLUSIONS: To increase the likelihood that a patient safety event will be voluntarily reported, our study suggests placing priority on improving event feedback mechanisms and communication of event-related improvements. Focusing efforts on these aspects may be more efficient than other forms of culture change.

The association of mediastinal mass in the formation of thrombi in pediatric patients with non-lymphoblastic lymphomas.

BACKGROUND: Children diagnosed with cancer are at a significantly higher risk of developing a thrombotic event (TE) compared with the general population. The rarity of these events makes it difficult to discern the specific risk factors; however, age, sex, presence of central venous lines, inherited thrombophilia, and mediastinal mass may play a role. The primary aim of this study is to identify prognostic characteristics of children diagnosed with non-lymphoblastic lymphomas associated with a greater risk of developing a TE early on in their disease, with an increased focus on mediastinal mass characteristics. METHODS: Retrospective chart review of pediatric patients diagnosed with non-lymphoblastic lymphoma between 2004 and 2014 at St. Jude Children's Research Hospital. RESULTS: TE occurred in 8.5% (n = 28/330) of individuals at a median of 21 days from the diagnosis of a non-lymphoblastic lymphoma, with 60% of TEs occurring within 30 days of diagnosis. Of the variables evaluated, only presence of a peripherally inserted central catheter (odds ratio [OR]: 3.14 [95% CI: 1.24-7.98; P = 0.02]) and degree of superior vena cava (SVC) compression of > 25% increased the odds of developing a TE (OR: 2.2 [95% CI: 1.01-4.93; P = 0.048]). CONCLUSION: Pediatric patients with non-lymphoblastic lymphoma are at increased risk of developing TEs. In contrast to previous studies, the presence of a mediastinal mass alone was not associated with a higher risk of TE, but individuals with a mediastinal mass with 25% or greater degree of SVC compression were more likely to develop a TE. This finding highlights a high-risk group of children who may benefit from prophylactic anticoagulation.

Ecological principle meets cancer treatment: treating children with acute myeloid leukemia with low-dose chemotherapy.

Standard chemotherapy regimens for remission induction of pediatric acute myeloid leukemia (AML) are associated with significant morbidity and mortality. We performed a cohort study to determine the impact of reducing the intensity of remission induction chemotherapy on the outcomes of selected children with AML treated with a low-dose induction regimen plus granulocyte colony stimulating factor (G-CSF) (low-dose chemotherapy (LDC)/G-CSF). Complete response (CR) after two induction courses was attained in 87.0% (40/46) of patients receiving LDC/G-CSF. Post-remission therapy was offered to all patients, and included standard consolidation and/or stem cell transplantation. During the study period, an additional 94 consecutive children with AML treated with standard chemotherapy (SDC) for induction (80/94 (85.1%) of the patients attained CR after induction II, P = 0.953) and post-remission. In this non-randomized study, there were no significant differences in 4-year event-free (67.4 vs. 70.7%; P = 0.99) and overall (70.3 vs. 74.6%, P = 0.69) survival in the LDC/G-CSF and SDC cohorts, respectively. After the first course of induction, recovery of white blood cell (WBC) and platelet counts were significantly faster in patients receiving LDC/G-CSF than in those receiving SDC (11.5 vs. 18.5 d for WBCs (P < 0.001); 15.5 vs. 22.0 d for platelets (P < 0.001)). To examine the quality of molecular response, targeted deep sequencing was performed. Of 137 mutations detected at diagnosis in 20 children who attained hematological CR after two courses of LDC/G-CSF (n = 9) or SDC (n = 11), all of the mutations were below the reference value (variant allelic frequency <2.5%) after two courses, irrespective of the treatment group. In conclusion, children with AML receiving LDC/G-CSF appear to have similar outcomes and mutation clearance levels, but significantly lower toxicity than those receiving SDC. Thus, LDC/G-CSF should be further evaluated as an effective alternative to remission induction in pediatric AML.

Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have an increased risk of obesity and short stature. To the authors' knowledge, data regarding patients treated on contemporary protocols without cranial irradiation are limited. METHODS: Changes in z scores for body mass index (BMI), height, and weight from the time of diagnosis to 5 years off therapy were evaluated using multivariable analysis in 372 children with ALL who were aged 2 to 18 years at the time of diagnosis and were enrolled on the St. Jude Children's Research Hospital Total XV protocol from 2000 through 2007. RESULTS: The percentage of overweight/obese patients increased from 25.5% at the time of diagnosis to approximately 50% during the off-therapy period. Median BMI z scores increased significantly during glucocorticoid therapy (induction: ∆0.56; 95% confidence interval [95% CI], 0.29-0.64 [P<.001]; and reinduction II: ∆0.22; 95% CI, 0.13-0.49 [P=.001]) and during the first year after therapy (∆0.18; 95% CI, 0.08-0.46 [P=.006]). Among patients who were of healthy weight/underweight at the time of diagnosis, those aged 2 to <10 years at diagnosis had a significantly higher risk of becoming overweight/obese during or after therapy compared with those aged ≥10 years (P=.001). Height z scores declined during treatment and improved after therapy. Being aged 2 to <10 years at the time of diagnosis, being of low-risk status, having a white blood cell count < 50×109 /L at the time of diagnosis, and having negative central nervous system disease were associated with significantly better improvements in z scores for height during the off-therapy period compared with being aged ≥10 years, being of standard-risk/high-risk status, having a white blood cell count ≥ 50×109 /L, and having positive central nervous system disease, respectively. CONCLUSIONS: The results of the current study demonstrate that obesity is prevalent, and height growth, especially in patients with identified risk factors, appears compromised. Multidisciplinary intervention should begin during induction therapy and continue during the off-therapy period.

CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss.

Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration-approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss. CDK2-deficient mice displayed enhanced resistance to cisplatin toxicity in cochlear explants and to cisplatin- and noise-induced hearing loss in vivo. Mechanistically, we showed that kenpaullone directly inhibits CDK2 kinase activity and reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing cell survival. Our experiments have revealed the proapoptotic function of CDK2 in postmitotic cochlear cells and have identified promising therapeutics for preventing hearing loss.

Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia.

BACKGROUND: Limited information is available regarding neurocognitive outcomes of children who experience seizures during treatment for acute lymphoblastic leukemia (ALL). Accordingly, the main objectives of this study were to determine the incidence and risk factors for treatment-related seizures among children with ALL, and the neurocognitive outcomes associated with treatment-related seizures. PROCEDURE: Prospective neuropsychological assessment and magnetic resonance imaging (MRI) were planned for all 498 patients with newly diagnosed ALL enrolled on the St. Jude Total Therapy XV (TOTXV) protocol at three time points. The study database was reviewed retrospectively to identify those with treatment-related seizure. To assess neurocognitive changes associated with seizure, each patient with treatment-related seizure was matched with two cohort patients without seizure for age at treatment, gender, race, and treatment intensity. RESULTS: Nineteen patients developed seizure, with a 2-year cumulative risk of 3.82 ± 0.86% (SE). No risk factors were identified to be associated with the development of seizure, with a possible exception of intensive chemotherapy used on the standard/high-risk arm as compared to the low-risk arm. Neuropsychological performance of the seizure group, as compared to normative scores and nonseizure control cohort, indicated problems in attention, working memory, and processing speed. Cognitive deficits persisted 2 years after therapy, with additional declines in intellectual function observed. MRI indicated early neurotoxicity among the seizure group, as evidenced by greater leukoencephalopathy on initial examinations. CONCLUSION: Treatment-related seizures were associated with leukoencephalopathy and decreased neuropsychological performance. Prospective studies are needed to detect changes in neurocognitive status associated with long-term functional impairment.

The Role of Leukapheresis in the Current Management of Hyperleukocytosis in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Hyperleukocytosis in children with acute lymphoblastic leukemia (ALL) has been associated with early morbidity and mortality. The use of leukapheresis in these children treated with contemporary therapy remains controversial. PROCEDURE: We analyzed clinical data from patients enrolled onto frontline protocols for ALL (Total Therapy XV and XVI) between 2003 and 2014. We documented adverse events within the first 14 days in patients with a white blood cell (WBC) count ≥200 × 10(9) /l and reviewed their management. RESULTS: Fifty-three (7.8%) of 678 consecutive pediatric patients with newly diagnosed ALL presented with hyperleukocytosis (median WBC count 393 × 10(9) /l; range 200-1,014). Two deaths in patients without initial hyperleukocytosis occurred within the first 2 weeks from diagnosis secondary to bacterial sepsis. A total of 21 (40%) patients with ALL and hyperleukocytosis developed grade 3 or 4 adverse events regardless of the use of leukapheresis (P > 0.99 and P = 0.19). Sixteen of 53 (30%) patients with ALL received low-dose chemotherapy for leukocytoreduction initially. One-third of patients received urate oxidase, and none of the patients with hyperleukocytosis required hemodialysis. CONCLUSIONS: The early morbidity and mortality commonly associated with hyperleukocytosis in children with newly diagnosed ALL can be avoided with contemporary supportive care and conservative management possibly obviating the need for costly and potentially dangerous leukapheresis.

Acute respiratory infections in children and adolescents with acute lymphoblastic leukemia.

BACKGROUND: Knowledge regarding the incidence, clinical course, and impact of respiratory viral infections in children with acute lymphoblastic leukemia (ALL) is limited. METHODS: A retrospective cohort of patients with newly diagnosed ALL who were treated on the Total Therapy XVI protocol at St Jude Children's Research Hospital between 2007 and 2011 was evaluated. RESULTS: Of 223 children, 95 (43%) developed 133 episodes of viral acute respiratory illness (ARI) (incidence, 1.1 per 1000 patient-days). ARI without viral etiology was identified in 65 patients (29%) and no ARI was detected in 63 patients (28%). There were no significant associations noted between race, sex, age, or ALL risk group and the development of ARI. Children receiving induction chemotherapy were found to be at the highest risk of viral ARI (incidence, 2.3 per 1000 patient-days). Influenza virus was the most common virus (38%) followed by respiratory syncytial virus (33%). Of 133 episodes of viral ARI, 61% of patients were hospitalized, 26% experienced a complicated course, 80% had their chemotherapy delayed, and 0.7% of patients died. Twenty-four patients (18%) developed viral lower respiratory tract infections (LRTI), 5 of whom (21%) had complications. Patients with viral LRTI had a significantly lower nadir absolute lymphocyte count; were sicker at the time of presentation; and were more likely to have respiratory syncytial virus, to be hospitalized, and to have their chemotherapy delayed for longer compared with those with viral upper respiratory tract infections. CONCLUSIONS: Despite the low incidence of viral ARI in children with ALL, the associated morbidity, mortality, and delay in chemotherapy remain clinically significant. Viral LRTI was especially associated with high morbidity requiring intensive care-level support. Cancer 2016;122:798-805. © 2015 American Cancer Society.

Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study.

Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age ≤18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% ± 2.7% and 49.0% ± 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = .037) and OS (P = .003) than those diagnosed in 1989 to 1999. Transplantation in first remission did not improve survival. Cytogenetic data were available for 372 (75.9%) patients: hypodiploid (n = 18, 4.8%), normal karyotype (n = 49, 13.2%), pseudodiploid (n = 119, 32.0%), 47 to 50 chromosomes (n = 142, 38.2%), and >50 chromosomes (n = 44, 11.8%). Chromosome gain occurred in 195 of 372 (52.4%) patients: +21 (n = 106, 28.5%), +19 (n = 93, 25.0%), +8 (n = 77, 20.7%). Losses occurred in 65 patients (17.5%): -7 (n = 13, 3.5%). Common structural chromosomal aberrations were t(1;22)(p13;q13) (n = 51, 13.7%) and 11q23 rearrangements (n = 38, 10.2%); t(9;11)(p22;q23) occurred in 21 patients. On the basis of frequency and prognosis, AMKL can be classified to 3 risk groups: good risk-7p abnormalities; poor risk-normal karyotypes, -7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, -13/13q-, and -15; and intermediate risk-others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes.