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Background/objectives: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial., Methods: Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival., Results: Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008)., Conclusion: We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase., (© 2022 Wiley Periodicals LLC.)

Patients with therapy-refractory or high-risk relapsed classical Hodgkin lymphoma are typically treated with the high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4 years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients., (© 2022 Wiley Periodicals LLC.)

The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: There have been remarkable advances in overall survival following the diagnosis of acute lymphoblastic leukemia in childhood, but toxicities, including pancreatitis, remain a concern. Pancreatitis occurs early in therapy, before extensive exposure to the chemotherapy agents associated with its development, indicating there are underlying risk factors for some children. The role of race/ethnicity in treatment-related pancreatitis has not been well established., Objective: The aim of this study was to examine the relationship between race/ethnicity and pancreatitis in children hospitalized with acute lymphoblastic leukemia in the United States in 2016., Methods: This was an analysis of a nationally representative database of pediatric hospitalizations. The sample consisted of 21 775 records with documentation of the diagnosis of acute lymphoblastic leukemia. Statistical methods included descriptive statistics, bivariate analyses using the χ2 test, and multilevel logistic regression models., Results: Pancreatitis was documented in 1.6% of hospital discharges. Compared with white children, Hispanic children were at increased risk of pancreatitis during hospitalization (P = .002). There were no differences among black (P = .469), Asian (P = .364), or other-race children (P = .937)., Conclusions: Hispanic children hospitalized with acute lymphoblastic leukemia are at greater risk of pancreatitis than white children. Reasons for this disparity are likely due to both genetic and social factors., Implications for Practice: Nurses must be active participants in the research process with the goal of enrolling patients with diverse backgrounds in clinical trials. Inclusive research will provide increased understanding of a holistic toxicity risk profile., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase., Methods: Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m 2 /dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose., Results: Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( P = .65)., Conclusion: Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized., Competing Interests: Traci M. BlonquistStock and Other Ownership Interests: JNJ, Pfizer Jeffrey G. SupkoEmployment: Ono PharmaceuticalResearch Funding: Constellation Pharmaceuticals Kara M. KellyResearch Funding: MerckTravel, Accommodations, Expenses: Bristol Myers Squibb Andrew E. PlaceConsulting or Advisory Role: NovartisResearch Funding: Novartis Donna S. NeubergStock and Other Ownership Interests: Madrigal PharmaceuticalsResearch Funding: Pharmacyclics Stephen E. SallanConsulting or Advisory Role: SyndaxTravel, Accommodations, Expenses: Syndax Lewis B. SilvermanConsulting or Advisory Role: Servier, Syndax, Jazz PharmaceuticalsResearch Funding: ServierNo other potential conflicts of interest were reported.

Purpose: The COVID-19 pandemic has significantly affected the well-being of healthcare workers to varying degrees. The aim of the current study was to investigate how the pandemic has affected the burnout, stress, and emotional well-being of pediatric hematology oncology (PHO) providers and staff in the New York and New Jersey epicenter., Methods: The study was conducted in June 2020 during the pandemic through an electronic survey. The survey contained questions surrounding demographics, pandemic experiences, and validated burnout, stress, and emotional well-being measures., Results: Two hundred fifty-two PHO providers and staff responded to the survey. Overall, half of the participants reported high levels of burnout, average stress scores were in the mild-moderate range, and the majority scored in the none-to-mild symptomatology range for their well-being. Self-reported burnout levels before the pandemic and geographic work location were statistically significant risk factors for all outcomes. Additional predictors for some outcomes included hospital role, lack of trust in leadership, and deployment. The majority of participants (87.0%) reported that their hospitals had made mental health resources related to COVID-19 available to them but only 8.4% reported having used them., Conclusion: PHO providers and staff in the NYC/NJ area are experiencing a range of emotional experiences during the COVID-19 pandemic, but the majority are not using current resources. With the continuation of the pandemic, we must continue efforts to improve provider and staff distress to mitigate the degree of potential negative short-term and long-term impact., Competing Interests: Adam S. LevyConsulting or Advisory Role: AstraZenecaNo other potential conflicts of interest were reported.

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 ., (©2021 American Association for Cancer Research.)

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms., (© 2021 by The American Society of Hematology.)

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutritional morbidities are a persistent problem facing pediatric patients during and after treatment and age-gender groups that are at risk for nutritional conditions have not been clearly identified. Therapy is a contributing factor; however, the role of dietary intake remains largely unknown. Prior to conduct of interventional trials, an understanding of the effects of treatment on fluctuations in dietary intake is necessary., Methods: We enrolled 794 children with ALL in a prospective clinical trial. Dietary intake was collected with a food frequency questionnaire at diagnosis and throughout the course of treatment for pediatric ALL. Reported values were compared to the Dietary Recommended Intake (DRI), and normative values (NHANES). Hierarchical linear models and multilevel mixed-effects ordered logistic regression models were used to evaluate longitudinal changes in dietary intake; independent samples t-test with Bonferroni correction was performed to compare to NHANES., Results: Of the evaluable participants at each timepoint, dietary intake was obtained on 81% (n = 640), 74% (n = 580) and 74% (n = 558) at diagnosis, end of induction phase of treatment, and continuation, respectively. Despite exposure to corticosteroids, caloric intake decreased over therapy for most age-gender groups. Predictive models of excess intake found reduced odds of over-consuming calories (OR 0.738, P < 0.05); however, increased odds of over-consuming fat (OR 6.971, P < 0.001). When compared to NHANES, we consistently found that ≥1/3 of children were consuming calories in excess of normative values. For select micronutrients, a small proportion of participants were above or below the DRI at each time evaluated., Conclusions: Our study suggests that dietary intake fluctuates during treatment for ALL as compared to age-gender recommended and normative values. Improving our understanding of nutrient fluctuations and dietary quality will facilitate subsequent analyses addressing relationships of dietary intake, toxicity, and survival., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse., Methods: In this Children's Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m 2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662., Findings: Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m 2 . 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths., Interpretation: Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials., Funding: National Institutes of Health and the St. Baldrick's Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10 -3 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics ( KMT2A rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy. IKZF1 deletion status was retrospectively evaluated by multiplex ligation-dependent probe amplification. Between 2005 and 2011, 678 Philadelphia chromosome-negative B-ALL patients aged 1 to 18 years enrolled; 651 achieved CR and 648 received a final risk group. Among all 678 patients, 5-year event-free survival (EFS) was 87% (95% confidence interval [CI], 84-89) and overall survival 93% (95% CI, 90-94). Five-year disease-free survival of SR patients (N = 407) was 94% (95% CI, 91-96), HR (N = 176) was 84% (95% CI, 77-88), and VHR (N = 65) was 79% (95% CI, 67-87). IKZF1 deletion was present in 62 of 385 (16%) assessed patients and was associated with inferior 5-year EFS (63%; 95% CI, 49%-74% vs 88%; 95% CI, 84%-91%; P < .001), and higher 5-year cumulative incidence of relapse, including among those with low MRD (24% vs 8%, P = .001). In multivariable analysis, age ≥15 years, WBC ≥50 × 10 9 /L, IKZF1 deletion, and MRD ≥10 -4 was each associated with inferior outcome. In conclusion, risk-stratified therapy on DFCI 05-001 resulted in favorable outcomes for B-ALL patients, including those with VHR features. IKZF1 deletion was an independent predictor of inferior outcome. This trial was registered at www.clinicaltrials.gov as #NCT00400946., (© 2018 by The American Society of Hematology.)

Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion ( ETV6-ABL1 : n = 1; FOXP1-ABL1 : n = 1; SFPQ-ABL1 : n = 1; ZC3HAV1-ABL2 : n = 1) or a fusion activating the JAK-STAT pathway ( P2RY8-CRLF2 : n = 8; PAX5-JAK2 : n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1 -altered patients, irrespective of the presence of a kinase-activating fusion., (© 2018 by The American Society of Hematology.)

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 μM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.

Purpose of Review: The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL)., Recent Findings: Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

Objective: Children with acute lymphoblastic leukemia (ALL) are at elevated risk for nutrition-related morbidity both during and after therapy. We present the demographic characteristics and nutrient intake at study entry of a prospective cohort in which evaluating dietary intake in children diagnosed with ALL was investigated., Methods: Dietary intake data were collected for participants enrolled on the Dana-Farber Cancer Institute ALL Consortium Protocol. Dietary intake was assessed with a food frequency questionnaire and was compared with the dietary reference intake by ALL risk group (standard and high risk)., Results: Dietary intake data were collected from 81% of participants (n = 640). We found that 27% of participants were overweight/obese. Intake of total calories and other nutrients exceeded the dietary reference intake in up to 79% of children. This was evident in both risk groups and was pronounced among younger children. For micronutrients, dietary intake of calcium, vitamin D (females only), and zinc differed significantly between patients with standard-risk and those with high-risk ALL., Conclusions: This study was successful in collecting dietary intake data at the time of cancer diagnosis in a multicenter setting in a pediatric population at high-risk for nutrition-related morbidity. We identified "at-risk" dietary intakes, which vary by sex and ALL risk group; such patients may benefit from future dietary interventions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

γ-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain folylpolyglutamates are associated with functionally significant DNA methylation alterations in several important biological pathways.

The neurotoxic effects of therapy for childhood acute lymphoblastic leukemia can result in leukoencephalopathy or measurable deficits in cognitive function. However, there are no validated biomarkers that allow the identification of those patients at greatest risk. With the objective of identifying such predictors, cerebrospinal fluid collected from 53 patients over 2.5 years of therapy for childhood acute lymphoblastic leukemia was retrospectively studied. Cerebrospinal fluid folate, concentrated relative to serum folate prior to therapy, dropped during the first month of therapy and remained below baseline throughout treatment. Cerebrospinal fluid homocysteine was inversely related to cognitive function prior to treatment. Oral methotrexate was associated with decreased cerebrospinal fluid folate and increased cerebrospinal fluid homocysteine, but these changes were not seen with oral aminopterin. Of 36 patients who had imaging after completion of therapy, 9 had periventricular or subcortical white matter abnormalities consistent with leukoencephalopathy. Peak cerebrospinal fluid tau concentrations during therapy were higher among patients who had leukoencephalopathy after completion of therapy than among those with normal imaging studies at the end of therapy. If confirmed prospectively, these markers may allow the identification of those patients at greatest risk of developing treatment-induced neurocognitive dysfunction, thus guiding preventive interventions.

Purpose: Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients' blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL., Experimental Design: Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m(2), in two doses 12 h apart, in place of methotrexate 100 mg/m(2) in four divided doses., Results: Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase., Conclusions: Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.

Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including craniospinal irradiation, nucleoside analogs, corticosteroids, and antifolates. In this review, we describe the characteristic radiographic findings and neurocognitive deficits seen among survivors of childhood ALL. We summarize what is known about the pathophysiology of delayed treatment-related neurotoxicity, with a focus on the toxicity resulting from pharmacologic disruption of folate physiology within the central nervous system. Finally, we suggest testable strategies to ameliorate the symptoms of treatment-related neurotoxicity or decrease its incidence., (Copyright 2006 Wiley-Liss, Inc.)