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Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN., (© 2023 Wiley Periodicals LLC.)

Background: Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs)., Procedures: Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-Prkdc scid IL2rg tm1Wjl /SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45 + cells (%huCD45 + ) in the peripheral blood. Treatment commenced when the %huCD45 + reached greater than or equal to 1%, and events were predefined as %huCD45 + greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event-free survival and stringent objective response measures., Results: PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values <.0001). Duvelisib was well-tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent., Conclusions: Duvelisib demonstrated limited in vivo activity against ALL PDXs., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs)., Methods: SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45 + cells (%huCD45 + ) in the peripheral blood. TAK-659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45 + ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event-free survival and stringent objective response measures., Results: FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45 + was significantly reduced in five out of eight PDXs in TAK-659-treated mice compared with vehicle controls., Conclusions: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes., (© 2023 Wiley Periodicals LLC.)

Thromboembolism is a serious toxicity in the treatment of acute lymphoblastic leukemia (ALL), but little is known about the correlation between asparaginase enzyme activity (ASA) levels and coagulation parameters. We included 65 non-high risk ALL patients, aged 1-17 years. Coagulation parameters and corresponding ASA levels were measured during asparaginase treatment. We found ASA to be negatively correlated with antithrombin and fibrinogen up to ASA levels of 250 IU/L, after which these parameters reached a plateau and did not decrease further with further increase of ASA. Patients with silent inactivation of asparaginase had normal coagulation parameters., (© 2022 Wiley Periodicals LLC.)

RAS mutations are frequently observed in childhood B-cell acute lymphoblastic leukemia (B-ALL) and previous studies have yielded conflicting results as to whether they are associated with a poor outcome. We and others have demonstrated that the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK) pathway can be activated through epigenetic mechanisms in the absence of RAS pathway mutations. Herein, we examined whether MAPK activation, as determined by measuring phosphorylated extracellular signal-regulated kinase (pERK) levels in 80 diagnostic patient samples using phosphoflow cytometry, could be used as a prognostic biomarker for pediatric B-ALL. The mean fluorescence intensity of pERK (MFI) was measured at baseline and after exogenous stimulation with or without pretreatment with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Activation levels (MFI stimulated/MFI baseline) ranged from 0.76 to 4.40 (median = 1.26), and inhibition indexes (MFI stimulated/MFI trametinib stimulated) ranged from 0.439 to 5.640 (median = 1.30), with no significant difference between patients with wildtype versus mutant RAS for either. Logistic regression demonstrated that neither MAPK activation levels nor RAS mutation status at diagnosis alone or in combination was prognostic of outcome. However, 35% of RAS wildtype samples showed MAPK inhibition indexes greater than the median, thus raising the possibility that therapeutic strategies to inhibit MAPK activation may not be restricted to patients whose blasts display Ras pathway defects., (© 2022 Wiley Periodicals LLC.)

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003)., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of neurocognitive weakness in the areas of attention, executive function, and processing speed. Although fatigue and sleep disturbances are frequent complications of ALL therapy and associated with cognitive functions, the impact of fatigue and sleep profiles during active ALL treatment on posttreatment neurocognitive performance has received limited attention., Methods: Pediatric patients (n = 120) with ALL (diagnosed 2011-2016) who completed fatigue and sleep questionnaires at four time points during active treatment were enrolled in a study of neurocognitive performance. Latent class growth analysis identified subgroups of patients with similar sleep and fatigue profiles during treatment. Neurocognitive performance collected >6 months post treatment on 40 participants was compared between latent classes using multivariable linear regression models., Results: Participants (57.5% male and 79.1% Hispanic or non-Hispanic White) were classified into one of two fatigue and sleep profiles: Class 1 characterized by mild fatigue and sleep disturbances during treatment (50.8%), and Class 2 characterized by higher levels of fatigue and sleep disturbances (49.2%). Posttreatment cognitive performance was in the normal range for most measures, but significantly below normative means for executive function, verbal short-term memory, attention, and distractability measures. Compared to Class 1, Class 2 demonstrated significantly (p < .05) poorer posttreatment neurocognitive performance, particularly in measures of attention., Conclusions: Our findings indicate that fatigue and sleep disturbances during the first year of pediatric ALL therapy may impact long-term neurocognitive performance. Sleep and fatigue may be targets for intervention to preserve cognitive functioning in survivors., (© 2021 Wiley Periodicals LLC.)

Introduction: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended., Methods: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy., Results: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21., Conclusion: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

We report a retrospective analysis of 110 unselected pediatric patients with acute lymphoblastic leukemia (ALL) treated during 2015-2017 in a charity-funded public institution in Cambodia with a reduced intensity ALL-Moscow Berlin (MB)-91 protocol. No patient abandoned treatment. Sixty-three patients (57%) were high risk (HR). Seventy-two patients (65.5%) reached complete remission (CR) on day 36. The 3-year event-free survival (EFS) and overall survival (OS) was 34.9% (50.5% for standard risk [SR]). Most deaths resulted from infections (40 [53.3%]) and bleeding (15 [20%]). With further selective reduction of treatment intensity and access to platelet infusion, leukemia therapy is justified in this setting., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Carboxypeptidase G 2 (CPDG 2 ; glucarpidase) is a rescue drug for patients at risk for kidney injury from high-dose methotrexate (MTX). As there are no strategies for predicting patients who will require CDPG 2 , we evaluated the role of demographic, clinical, and genetic factors for CPDG 2 use., Procedure: Cases who received CPDG 2 and controls who did not were identified by chart review of acute lymphoblastic leukemia (ALL) patients who received MTX doses between 1000 and 5000 mg/m 2 between 2010 and 2017. We used multivariable Bayesian logistic regression to evaluate the association of CPDG 2 use with demographic and clinical variables and, on a subset of patients, with genetic ancestry and 49 single nucleotide variants previously associated with MTX toxicity., Results: We identified 423 patients who received 1592 doses of MTX. Of the 18 patients who received CPDG 2 , 17 (94%) were Hispanic. No patients who received 1000 or 2000 mg/m 2 of MTX received CPDG 2 . Hispanic ethnicity (odds ratio: 4.68; 95% compatibility interval: 1.63-15.06) and older age (1.87 [1.17-3.17]) were associated with receiving CPDG 2 . Of the 177 patients in the genomic cohort, 11 received CPDG 2 . Each additional G allele of rs7317112 in ABCC4 increased the odds of requiring CPDG 2 (3.10 [1.12-6.75]). Six other loci (NTRK1/rs10908521, TSG1/rs9345389, STT3B/rs1353327, SCLO1B1/rs4149056, GATA3/rs3824662, ARID5B/rs10821936) demonstrated probabilities of association between 88% and 97%., Conclusion: We demonstrated that demographic characteristics, including Hispanic ethnicity and age, are associated with CPDG 2 use. Additionally, we provide evidence that inherited genetic variation is associated with risk of requiring CPDG 2 . If validated in independent populations, this information could be leveraged to develop targeted toxicity prevention strategies for children with ALL., (© 2021 Wiley Periodicals LLC.)

Background: The efficacy and safety of recombinant Escherichia coli-asparaginase (rASNase) was compared to native E.coli asparaginase (Asparaginase medac)., Methods: One hundred and ninety-nine children with newly diagnosed acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5,000 U/m² during induction (eight doses) and 10,000 U/m² during the postinduction phase (only high-risk patients; standard- and medium-risk patients received pegaspargase)., Results: Median trough serum asparaginase activity levels were comparable between both groups; they ranged from 143 to 182 U/l during induction and were above the target value of 100 U/l. Complete asparagine depletion in serum was achieved in 97.9% of patients, with no significant differences between both groups. On day 33 (end of induction), only two (2%) evaluable patients in each group had measurable asparagine serum levels, and complete asparagine depletion in the cerebrospinal fluid was achieved in 98.8% and 93.6% of the patients with rASNase and Asparaginase medac, respectively. During induction, 2.1% and 5% of patients developed an allergic reaction to rASNase or Asparaginase medac, respectively. Approximately 41% of the patients in both groups had a clinical allergy or enzyme inactivation to the first dose of any asparaginase preparation in postinduction. A comparable proportion of patients in both groups developed anti-asparaginase antibodies (57%) during repeated administration of asparaginase. Minimal residual disease levels at the end of induction, 5-year event-free survival, and 5-year cumulative incidence of relapse did not differ between both groups., Conclusion: The efficacy, safety, and immunogenicity of both asparaginase preparations are comparable. This trial was registered at www.clinicaltrials.gov as #NCT00784017; EudraCT number 2006-003180-31., (© 2018 Wiley Periodicals, Inc.)

Background: The early effects of childhood acute lymphoblastic leukemia (ALL) include decreased physical function, bone mineral density (BMD/g/cm 2 ), and health-related quality of life (HRQL). We assessed the capacity of a physical therapy and motivation-based intervention, beginning after diagnosis and continuing through the end of treatment, to positively modify these factors., Procedure: A 2.5-year randomized controlled trial of 73 patients aged 4-18.99 years within 10 days of ALL diagnosis assessed BMD at baseline (T 0 ) and end of therapy (T 3 ), strength, range of motion, endurance, motor skills, and HRQL at baseline (T 0 ), 8 (T 1 ), 15 (T 2 ), and 135 (T 3 ) weeks., Results: There were no significant changes between groups (intervention, n = 33; usual care, n = 40) in BMD (P = 0.059) at T 3 or physical function and HRQL at T 0 -T 3 . While BMD declined in both the intervention (T 0  = -0.21, T 3  = -0.55) and usual care (T 0  = -0.62, T 3  = -0.78) groups, rates of decline did not differ between groups (P = 0.56). Univariate analysis (n = 73) showed associations of higher T 3 bone density with body mass index T 1 (P = 0.01), T 2 (P = <0.0001), T 3 (P = 0.01), T 3 ankle flexibility/strength (P = 0.001), and T 2 parent (P = 0.02)/T 0 child (P = 0.03) perceptions of less bodily pain., Conclusions: The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship., (© 2017 Wiley Periodicals, Inc.)

Background: We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians., Procedure: Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346)., Results: The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02)., Conclusions: Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL., (© 2017 Wiley Periodicals, Inc.)

Background: In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis., Procedure: We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes., Results: Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen., Conclusions: Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated., (© 2013 Wiley Periodicals, Inc.)

Background: The critical function of microRNAs in the pathogenesis and prognosis of hematopoietic cancer has become increasingly apparent. However, only a few miRNAs have been reported to be altered in acute lymphocytic leukemia (ALL)., Procedures: To uncover aberrantly expressed miRNAs in pediatric B-cell ALL, our study employed genome-wide miRNA microarray analysis and stem-loop real-time quantitative polymerase chain reaction (qRT-PCR) to examine common precursor B-cell ALL samples. The target genes of miRNA-708 were then identified and verified by bioinformatics, dual-luciferase reporter assay, qRT-PCR, and Western blot., Results: Significant upregulation of miR-708, miR-210, and miR-181b, and downregulation of miR-345 and miR-27a were observed in common precursor B-cell ALL (common-ALL) samples (P < 0.05). In addition, elevated expression of miR-708 and miR-181b were found in high-risk common-ALL compared to standard and intermediate ones. miR-708 inhibited luciferase reporter activity by binding to the 3'-untranslated regions (3'-UTRs) of CNTFR, NNAT, and GNG12 mRNA in HEK-293 cell line and suppressed the protein levels of CNTFR, NNAT, and GNG12 in Jurkat cells. In addition, mRNA levels of CNTFR and NNAT, but not of GNG12, were found to be downregulated in high risk common-ALL samples. Mutational analysis revealed that miR-708 binds to the 394-400 bp sequence region of the 3'-UTR of CNTFR mRNA., Conclusion: The expression level of miR-708 reflects differences among the clinical types of common-ALL, and CNTFR, NNAT, and GNG12 were identified as targets of miR-708., (© 2013 Wiley Periodicals, Inc.)