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1.  Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 
Journal of Clinical Oncology  2013;31(9):1202-1210.
Purpose
We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL).
Patients and Methods
Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m2 fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m2, adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.
Results
Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS.
Conclusion
There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.
doi:10.1200/JCO.2012.43.2070
PMCID: PMC3595424  PMID: 23358966
2.  Changes in Cardiac Biomarkers During Doxorubicin Treatment of Pediatric Patients With High-Risk Acute Lymphoblastic Leukemia: Associations With Long-Term Echocardiographic Outcomes 
Journal of Clinical Oncology  2012;30(10):1042-1049.
Purpose
Doxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately identifying cardiac injury and cardiomyopathy.
Patients and Methods
Children with high-risk ALL were randomly assigned to receive doxorubicin alone (n = 100; 75 analyzed) or doxorubicin with dexrazoxane (n = 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment.
Results
cTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P = .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P = .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P < .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P = .01). Increases in hsCRP were not associated with any echocardiographic variables.
Conclusion
cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.
doi:10.1200/JCO.2010.30.3404
PMCID: PMC3341148  PMID: 22370326
3.  Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 lysine 27 trimethylation 
Nature genetics  2014;46(6):618-623.
Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1 and polysomy 21 is the most frequent somatic aneuploidy amongst all B-ALLs2. Yet, the mechanistic links between chr.21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 confers murine progenitor B cell self-renewal in vitro, maturation defects in vivo, and B-ALL with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in progenitor B cells and B-ALLs, and “bivalent” genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q223–5, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.
doi:10.1038/ng.2949
PMCID: PMC4040006  PMID: 24747640
4.  Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia 
Cancer  2013;119(19):3555-3562.
Background
Doxorubicin is associated with progressive cardiac dysfunction, possibly by forming doxorubicin-iron complexes leading to free-radical injury. We determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia.
Methods
Peripheral blood was tested for two common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography.
Results
184 patients had DNA results for at least one variant, and 167 had both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (p=0.039), but not NT-proBNP. At a median of 2.2 years (1.0–3.6) after diagnosis, mean [SE] Z-scores for LV fractional shortening (−0.71 [0.25], p=0.008), mass (−0.84 [0.17], p<0.001), and end-systolic (−4.36 [0.26], p<0.001) and end-diastolic posterior wall thickness (−0.68 [0.25], p=0.01) were abnormal in children with either allele (n=32). Non-carriers (n=63) also had below-normal LV mass (−0.45 [0.15], p=0.006) and end-systolic posterior wall thickness (−4.06 [0.17], p<0.001). Later follow-up showed similar results.
Conclusions
Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly-diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity.
doi:10.1002/cncr.28256
PMCID: PMC3788065  PMID: 23861158
Cardiotoxicity; Doxorubicin; Hemochromatosis; Leukemia; Pediatrics
5.  Mutations in epigenetic regulators including SETD2 are gained during relapse in pediatric acute lymphoblastic leukemia 
Nature communications  2014;5:3469.
Relapsed pediatric acute lymphoblastic leukemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signaling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.
doi:10.1038/ncomms4469
PMCID: PMC4016990  PMID: 24662245
6.  Bim polymorphisms: influence on function and response to treatment in children with acute lymphoblastic leukemia 
Purpose
Corticosteroids (CS) induce apoptosis in the malignant lymphoid cells and are critical component of combination therapy for acute lymphoblastic leukemia (ALL). Several genome-wide microarray studies demonstrated major implication of proapoptotic Bim in mediating CS-related resistance in leukemia cells.
Experimental design
We investigated Bim gene polymorphisms and their association with childhood ALL outcome, and the mechanism underlying the observed finding.
Results
Lower overall survival (OS) was associated with Bim C29201T located in BH3 domain (p=0.01). An association remained significant in multivariate model (p=0.007), was more apparent in high risk (HR) patients (p=0.004) and patients treated with dexamethasone (p=0.009), and was subsequently confirmed in the replication patient cohort (p=0.03). RNA analysis revealed that C29201T affects generation of gamma isoforms (gamma1) that lack pro-apoptotic BH3 domain. The phenotypic effect was minor suggesting the influence of additional factors that may act in conjunction with Bim genotype. Combined analysis with Mcl gene polymorphism (G -486T) revealed profound reduction in OS in individuals with both risk genotypes (p<0.0005 in discovery and p=0.002 in replication cohort) and particularly in HR patients (p≤0.008).
Conclusions
Increased expression of pro-survival Mcl1 and presence of Bim isoforms lacking pro-apoptotic function might explain marked reduction of OS in a disease and dose dependent manner in ALL patients carrying Bim and Mcl1 risk genotypes.
doi:10.1158/1078-0432.CCR-13-1215
PMCID: PMC4128417  PMID: 23908358
corticosteroids; polymorphisms; Bim; Mcl1; apoptosis; pharmacogenetics; childhood leukemia; treatment; outcome
7.  Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes 
Pediatrics  2012;130(6):1003-1011.
BACKGROUND AND OBJECTIVES:
Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL).
METHODS:
The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m2 of doxorubicin in 30 mg/m2 doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function.
RESULTS:
A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24).
CONCLUSIONS:
In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.
doi:10.1542/peds.2012-0727
PMCID: PMC3507254  PMID: 23166343
anthracycline; cardiotoxicity; doxorubicin; leukemia; pediatrics
8.  Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000) 
The Dana-Farber Cancer Institute (DFCI) ALL Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20–30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985–2000, 1457 children aged 0–18 years were treated on four consecutive protocols: 85-01 (1985–7), 87-01 (1987–91), 91-01 (1991–5) and 95-01 (1996–2000). The 10-year event-free survival (EFS) ± standard error by protocol was 77.9 ± 2.8% (85-01), 74.2± 2.3 (87-01), 80.8 ± 2.1% (91-01) and 80.5 ± 1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (p=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79–85% for T-ALL patients and 75–78% for adolescents (age 10–18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely impacting EFS or OS in high-risk patients and frequently-dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.
doi:10.1038/leu.2009.253
PMCID: PMC2820141  PMID: 20016537
Acute lymphoblastic leukemia; long-term follow-up; asparaginase; anthracycline
9.  Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial 
The lancet oncology  2010;11(10):950-961.
Summary
Background
Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment.
Methods
Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087.
Findings
100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: −0·82, 95% CI −1·31 to −0·33; end-systolic dimension: 0·57, 0·21–0·93) but not for those who also received dexrazoxane (−0·41, −0·88 to 0·06; 0·15, −0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46–0·48) and thickness-to-dimension ratio (0·66, 0·64–0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24–2·11), but not in boys (−0·10, −0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44–1·85), but not in boys (0·19, −0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3–12·1), event-free survival was 77% (95% CI 67–84) for children in the doxorubicin-alone group, and 76% (67–84) for children in the doxorubicin plus dexrazoxane group (p=0·99).
Interpretation
Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys.
Funding
US National Institutes of Health, Children’s Cardiomyopathy Foundation, University of Miami Women’s Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.
doi:10.1016/S1470-2045(10)70204-7
PMCID: PMC3756093  PMID: 20850381
10.  The Low Incidence of Secondary Acute Myelogenous Leukemia in Children and Adolescents Treated with Dexrazoxane for Acute Lymphoblastic Leukemia: A Report from the Dana-Farber Cancer Institute ALL Consortium 
Summary
Background
Dexrazoxane reduces the risk of anthracycline-related cardiotoxicity. In a study of children with Hodgkin lymphoma, the addition of dexrazoxane may have been associated with a higher risk for developing second malignant neoplasms (SMNs) including acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). We determined the incidence of SMNs in children and adolescents with acute lymphoblastic leukemia (ALL) who were treated with dexrazoxane.
Methods
Between 1996 and 2010, the Dana-Faber Cancer Institute ALL Consortium conducted three consecutive multicenter trials for children with newly diagnosed ALL. In the first (1996–2000), high risk patients were randomly assigned to receive doxorubicin (30 mg/m2/dose, cumulative dose 300mg/m2) preceded by dexrazoxane (300 mg/m2/dose, 10 doses), or the same dose of doxorubicin without dexrazoxane, during induction and intensification phases. In subsequent trials (2000–2005 and 2005–2010), all high risk and very high risk patients received doxorubicin preceded by dexrazoxane. Cases of SMNs were collected prospectively and were pooled for analysis. The frequency and 5-year cumulative incidence (CI) of SMNs were determined for patients who had received dexrazoxane.
Findings
Among 553 patients treated with dexrazoxane (1996–2000, N=101; 2000–2005, N=196; and 2005–2010, N=256), the number of SMNs observed by protocol was 0 (median follow-up 9.6 years), 0 (median follow-up 5.2 years), and 1 (median follow-up 2.1 years). The only SMN was a case of AML, which developed in a patient with MLL-rearranged ALL 2.14 years after initial diagnosis. The overall 5-year CI of SMNs for all 553 patients was 0.24 ± 0.24%.
Interpretation
In a large population of children with high risk ALL who received dexrazoxane as a cardioprotectant drug, the occurrence of secondary AML was a rare event.
doi:10.1016/j.ejca.2011.03.022
PMCID: PMC3736806  PMID: 21514146
11.  Erwinia Asparaginase after Allergy to E coli Asparaginase in Children with Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2010;54(2):199-205.
Background
E coli asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity develops in up to 30% of patients. We assessed the nadir enzyme activity and tolerability of Erwinia asparaginase, an alternative preparation, in E coli asparaginase-allergic patients.
Patients and Methods
Between 2000-2002, 215 children with newly diagnosed ALL were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 and were to receive 30 weekly doses of intramuscular E coli asparaginase. If E coli asparaginase allergy developed, patients were switched to twice-weekly intramuscular Erwinia asparaginase (25,000 IU/m2). Nadir serum asparaginase activity (NSAA) was measured every 3 weeks.
Results
Forty-two patients (20%) developed E coli asparaginase allergy and switched to Erwinia. Of 38 patients with evaluable samples, 34 (89%) Erwinia-treated patients had at least one therapeutic NSAA (≥ 0.1 IU/mL). The median NSAA was 0.247 IU/mL 3 days and 0.077 IU/mL 4 days after an Erwinia dose. Associated toxicities included allergy in 14 (33%) and pancreatitis in 3 patients (7%). At a median follow-up of 5.4 years, event-free survival (± standard error) of the 42 patients who switched to Erwinia was 86 ± 5% compared with 81 ± 3% for the 170 patients without E coli asparaginase allergy (p= 0.55).
Conclusions
Twice-weekly Erwinia asparaginase was well-tolerated and achieved a therapeutically effective NSAA in most E coli-asparaginase allergic patients. Development of E coli allergy and subsequent treatment with twice-weekly Erwinia did not adversely impact event-free survival. Erwinia asparaginase should be considered for E coli asparaginase-allergic patients.
doi:10.1002/pbc.22225
PMCID: PMC3706086  PMID: 19672973
leukemia; childhood; asparaginase; Erwinia
12.  Neuropsychological Outcomes of Standard Risk and High Risk Patients Treated for Acute Lymphoblastic Leukemia on Dana-Farber ALL Consortium Protocol 95-01 at 5 Years Post Diagnosis 
Pediatric blood & cancer  2011;58(5):758-765.
Background
Children treated for acute lymphoblastic leukemia (ALL) as High Risk patients may be more vulnerable to neurocognitive late effects because of the greater intensity of their therapy. We compared neuropsychological outcomes in children treated for Standard Risk (SR) or High Risk (HR) ALL on Dana-Farber Cancer Institute (DFCI) Consortium ALL Protocol 95-01. We also evaluated their performance relative to normative expectations.
Procedure
Between 1996 and 2000, 498 children with newly diagnosed ALL were treated on Protocol 95-01, 298 of whom were eligible for neuropsychological follow-up. A feature of this protocol was modification of risk group criteria to treat more children as SR rather than HR patients, intended to minimize toxicities. Testing was completed at a median of 5.3 years post diagnosis for 211 patients (70.8%; ages 6 to 25 years; 45.5% male; 40% High Risk), all of whom were in continuous complete remission.
Results
Test scores for both groups were generally at or above normative expectation, with the exception of verbal working memory, processing complex visual information, and parent ratings of metacognitive skills. After adjusting for covariates, the SR group performed better on measures of IQ and academic achievement, working memory and visual learning. Effect sizes, however, were only in the small to moderate range.
Conclusions
HR patients exhibited neuropsychological deficits relative to SR patients, though the differences were modest in degree. Modification of the risk group criteria to treat more children on the SR protocol therefore likely afforded some benefit in terms of neurocognitive late effects.
doi:10.1002/pbc.23234
PMCID: PMC3189432  PMID: 21721112
acute lymphoblastic leukemia; neuropsychological; risk group; children
13.  Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia 
The New England Journal of Medicine  2012;366(15):1371-1381.
BACKGROUND
Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).
METHODS
We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients.
RESULTS
Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only.
CONCLUSIONS
Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.)
doi:10.1056/NEJMoa1110169
PMCID: PMC3374496  PMID: 22494120
14.  Neurobehavioral Side Effects of Corticosteroids During Active Treatment for Acute Lymphoblastic Leukemia in Children are Age-Dependent: Report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 
Pediatric blood & cancer  2011;57(3):492-498.
Background
Although corticosteroids remain a mainstay of treatment for acute lymphoblastic leukemia (ALL), they can cause troublesome neurobehavioral changes during active treatment, especially in young children. We evaluated acute neurobehavioral side effects of corticosteroid therapy in preschool versus school-age children by obtaining structured reports weekly for one month.
Procedure
Parents of 62 children (2 to 17 years at diagnosis) treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 00-01 participated during the continuation phase of treatment. Patients received cyclical twice-daily 5-day courses of prednisone (40 mg/m2/day) or dexamethasone (6 mg/m2/day). Parents completed behavior rating scales about their child weekly during one steroid cycle [baseline (Day 0), active steroid (Day 7), post-steroid (Days 14 and 21)].
Results
Behavioral side effects increased significantly (p < .001) during the steroid week for preschool children (< 6 years) on measures of emotional control, mood, behavior regulation, and executive functions, returning to baseline during the two ‘off-steroid’ weeks. In contrast, school-age children (≥ 6 years) did not demonstrate an increase in side effects during the steroid week. Steroid type (prednisone vs. dexamethasone) was not a significant predictor of neurobehavioral side effects.
Conclusions
Preschool children are at greater risk for neurobehavioral side effects during active steroid treatment for ALL than school age children and adolescents. Dexamethasone was not associated with more neurobehavioral side effects than prednisone. Counseling of families about side-effects should be adapted according to age. The observed effects, moreover, were transient, reducing concerns about longer-term neurobehavioral toxicities.
doi:10.1002/pbc.23060
PMCID: PMC3354622  PMID: 21560226
Pediatric hematology/oncology; ALL; chemotherapy neurotoxicities; corticosteroids; behavior
15.  Clinical Outcome of Children With Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Treated Between 1995 and 2005 
Journal of Clinical Oncology  2010;28(31):4755-4761.
Purpose
In a previous analysis of 326 children with Philadelphia chromosome (Ph) –positive acute lymphoblastic leukemia (ALL) treated between 1986 and 1996, hematopoietic stem-cell transplantation from HLA-matched related donors, but not from unrelated donors, offered a superior outcome than chemotherapy alone. To evaluate the impact of recent improvements in chemotherapy and transplantation, we performed a similar analysis on patients treated in the following decade.
Patients and Methods
We analyzed 610 patients with Ph-positive ALL treated between 1995 and 2005 without tyrosine kinase inhibitor therapy. The median follow-up duration was 6.3 years.
Results
Complete remission was achieved in 89% of patients. The 7-year event-free survival and overall survival rates were superior in the present cohort compared with the previous cohort (32.0% ± 2.0% v 25.0% ± 3.0, respectively, P = .007; and 44.9% ± 2.2% v 36.0% ± 3.0%, respectively, P = .017). Compared with chemotherapy alone, transplantation with matched related donors or unrelated donors in first remission (325 patients) showed an advantage with increasing follow-up, suggesting greater protection against late relapses (hazard ratio at 5 years, 0.37; P < .001). In the multivariate Cox regression analysis accounting for treatment (transplantation v no transplantation), age, leukocyte count, and early response had independent impact on treatment outcome.
Conclusion
Clinical outcome of children and adolescents with Ph-positive ALL has improved with advances in transplantation and chemotherapy. Transplantations with matched related donors and unrelated donors were equivalent and offered better disease control compared with chemotherapy alone. Age, leukocyte count, and early treatment response were independent prognostic indicators. The results of this study will serve as a historical reference to evaluate the therapeutic impact of tyrosine kinase inhibitors on the outcome of Ph-positive ALL.
doi:10.1200/JCO.2010.30.1325
PMCID: PMC3020705  PMID: 20876426
16.  Absence of Biallelic TCRγ Deletion Predicts Early Treatment Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2010;28(24):3816-3823.
Purpose
To identify children with T-cell acute lymphoblastic leukemia (T-ALL) at high risk of induction chemotherapy failure by using DNA copy number analysis of leukemic cells collected at diagnosis.
Patients and Methods
Array comparative genomic hybridization (CGH) was performed on genomic DNA extracted from diagnostic lymphoblasts from 47 children with T-ALL treated on Children's Oncology Group Study P9404 or Dana-Farber Cancer Institute Protocol 00-01. These samples represented nine patients who did not achieve an initial complete remission, 13 who relapsed, and 25 who became long-term, event-free survivors. The findings were confirmed in an independent cohort of patients by quantitative DNA polymerase chain reaction (DNA-PCR), an assay that is well suited for clinical application.
Results
Analysis of the CGH findings in patients in whom induction chemotherapy failed compared with those in whom induction chemotherapy was successful identified the absence of biallelic TCRγ locus deletion (ABD), a characteristic of early thymocyte precursors before V(D)J recombination, as the most robust predictor of induction failure (P < .001). This feature was also associated with markedly inferior event-free (P = .002) and overall survival (P < .001) rates: 25% versus 58% and 25% versus 72%, respectively. Using a rapid and inexpensive quantitative DNA-PCR assay, we validated ABD as a predictor of a poor response to induction chemotherapy in an independent series of patients.
Conclusion
Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRγ locus. Patients lacking biallelic deletion, which confers a high probability of induction failure with contemporary therapy, should be assigned to alternative therapy in the context of a prospective clinical trial.
doi:10.1200/JCO.2010.28.3390
PMCID: PMC2940399  PMID: 20644084
17.  Toxicity Assessment of Molecularly Targeted Drugs Incorporated into Multiagent Chemotherapy Regimens for Pediatric Acute Lymphocytic Leukemia (ALL): Review from an International Consensus Conference 
Pediatric blood & cancer  2010;54(7):872-878.
One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: 1) how toxicities can be best defined, assessed, and attributed; and 2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children’s Oncology Group (COG) ALL clinical trials.
doi:10.1002/pbc.22414
PMCID: PMC2857540  PMID: 20127846
ALL; ALL relapse; developmental therapeutics; dose-limiting toxicity; maximum tolerated dose
18.  Clinical Course and Outcome in Children with Acute Lymphoblastic Leukemia and Asparaginase-Associated Pancreatitis 
Pediatric blood & cancer  2009;53(2):162-167.
Background
Asparaginase, an agent used in the treatment of acute lymphoblastic leukemia (ALL), is associated with the development of pancreatitis. The clinical course and long-term outcome of patients experiencing this complication has not been extensively detailed.
Procedure
We reviewed the clinical course for all children with ALL diagnosed with pancreatitis at the Dana-Farber Cancer Institute/Children’s Hospital Boston between 1987 and 2003. The outcome of these patients was compared with that of patients with ALL who did not experience pancreatitis.
Results
Twenty-eight of 403 children (7%) were diagnosed with pancreatitis. Patients 10–18 years old at diagnosis had 2.4 times the risk of developing pancreatitis compared with younger patients. Pancreatitis typically occurred early in the course of therapy (median 4 weeks after first dose of asparaginase). Ninety-three percent of affected patients were hospitalized and 57% received parenteral nutrition. No patient developed chronic sequelae or died as a result of pancreatitis. Sixteen (57%) patients were retreated with asparaginase, 10 of whom had another episode of pancreatitis. No significant differences in event-free survival were observed when comparing patients with and without a history of pancreatitis.
Conclusion
Asparaginase-associated pancreatitis was more common in older children, and caused significant acute morbidity. It tended to occur after the first few doses of asparaginase, suggesting a predisposition to this complication rather than a cumulative drug effect. Re-treatment with asparaginase after an episode of pancreatitis was associated with a high risk of recurrent pancreatitis.
doi:10.1002/pbc.22076
PMCID: PMC2721691  PMID: 19405141
Asparaginase; Pancreatitis; Leukemia
19.  H3K79 methylation profiles define murine and human MLL-AF4 leukemias 
Cancer cell  2008;14(5):355-368.
Summary
We created a mouse model where conditional expression of an Mll-AF4 fusion oncogene induces B-precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 Lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. Human MLL-rearranged ALLs could be distinguished from other ALLs by their H3K79 profiles and suppression of the H3K79 methyltransferase DOT1L inhibited expression of critical MLL-AF4 target genes. We have thus demonstrated that ectopic H3K79 methylation is a distinguishing feature of murine and human MLL-AF4 ALLs and is important for maintenance of MLL-AF4 driven gene expression.
Significance
The t(4;11) encodes an MLL-AF4 fusion protein, and predicts a particularly poor prognosis when found in acute lymphoblastic leukemias (ALL). Recent studies suggest certain MLL-fusion proteins enhance gene expression by recruitment of the histone H3 lysine79 (H3K79) methyltransferase DOT1L. We demonstrate that H3K79 methylation is enhanced at many loci in leukemia cells from a murine model of Mll-AF4 and in human MLL-AF4 leukemia cells and this elevation is correlated with enhanced gene expression. Furthermore, suppression of H3K79 methylation leads to inhibition of gene expression in MLL-AF4 cells. These data demonstrate that inhibition of DOT1L may be a therapeutic approach in this disease, and that this mouse model should be useful for assessment of therapeutic approaches for MLL-rearranged ALL.
doi:10.1016/j.ccr.2008.10.001
PMCID: PMC2591932  PMID: 18977325
20.  Childhood leukemia: electric and magnetic fields as possible risk factors. 
Environmental Health Perspectives  2003;111(7):962-970.
Numerous epidemiologic studies have reported associations between measures of power-line electric or magnetic fields (EMFs) and childhood leukemia. The basis for such associations remains unexplained. In children, acute lymphoblastic leukemia represents approximately three-quarters of all U.S. leukemia types. Some risk factors for childhood leukemia have been established, and others are suspected. Pathogenesis, as investigated in animal models, is consistent with the multistep model of acute leukemia development. Studies of carcinogenicity in animals, however, are overwhelmingly negative and do not support the hypothesis that EMF exposure is a significant risk factor for hematopoietic neoplasia. We may fail to observe effects from EMFs because, from a mechanistic perspective, the effects of EMFs on biology are very weak. Cells and organs function despite many sources of chemical "noise" (e.g., stochastic, temperature, concentration, mechanical, and electrical noise), which exceed the induced EMF "signal" by a large factor. However, the inability to detect EMF effects in bioassay systems may be caused by the choice made for "EMF exposure." "Contact currents" or "contact voltages" have been proposed as a novel exposure metric, because their magnitude is related to measured power-line magnetic fields. A contact current occurs when a person touches two conductive surfaces at different voltages. Modeled analyses support contact currents as a plausible metric because of correlations with residential magnetic fields and opportunity for exposure. The possible role of contact currents as an explanatory variable in the reported associations between EMFs and childhood leukemia will need to be clarified by further measurements, biophysical analyses, bioassay studies, and epidemiology.
PMCID: PMC1241532  PMID: 12782499

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