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1.  Intrachromosomal Amplification of Chromosome 21 Is Associated With Inferior Outcomes in Children With Acute Lymphoblastic Leukemia Treated in Contemporary Standard-Risk Children's Oncology Group Studies: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2013;31(27):3397-3402.
Purpose
Five-year overall survival (OS) for children with B-cell precursor acute lymphoblastic leukemia (B-ALL) exceeds 90% with risk-adapted therapy. Age, initial WBC count, genetic aberrations, and minimal residual disease (MRD) are used for risk stratification. Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic lesion associated with inferior outcome in some studies. We investigated the impact of iAMP21 in a large cohort treated in contemporary Children's Oncology Group (COG) ALL trials.
Patients and Methods
Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. MRD was measured by flow cytometry at end induction. Outcome was measured as event-free survival (EFS) and OS.
Results
iAMP21 was found in 158 (2%) of 7,793 patients with B-ALL age ≥ 1 year; 74 (1.5%) of 5,057 standard-risk (SR) patients, and 84 (3.1%) of 2,736 high-risk (HR) patients. iAMP21 was associated with age ≥ 10 years, WBC less than 50,000/μL, female sex, and detectable MRD at day 29. Four-year EFS and OS were significantly worse for patients with iAMP21 and SR B-ALL, but iAMP21 was not a statistically significant prognostic factor in HR patients. There was no interaction between MRD and iAMP21. Among SR patients, day 29 MRD ≥ 0.01% and iAMP21 were associated with the poorest EFS and OS; absence of both was associated with the best outcome.
Conclusion
iAMP21 is associated with inferior outcome in pediatric B-ALL, particularly SR patients who require more intensive therapy and are now treated on HR COG ALL protocols.
doi:10.1200/JCO.2013.49.1308
PMCID: PMC3770866  PMID: 23940221
2.  Long-term Results Of the Pediatric Oncology Group Studies For Childhood Acute Lymphoblastic Leukemia 1984-2001: A Report From The Children’s Oncology Group 
Leukemia  2009;24(2):355-370.
From 1984-2001, the Pediatric Oncology Group (POG) conducted 12 acute lymphoblastic leukemia (ALL) studies. 10-year event free survival (EFS) for patients >12 months of age with B-precursor ALL on Acute Leukemia in Children 14, 15, and 16 series were 66.7 ± 1.2%, 68.1 ± 1.4% and 73.2 ± 2.1%, respectively. Intermediate dose methotrexate (ID MTX; 1 g/m2) improved outcomes for standard risk patients (10-year EFS 77.5 ± 2.7% vs. 66.3 ± 3.1% for oral MTX). Neither MTX intensification (2.5 g/m2) nor addition of cytosine arabinoside/daunomycin/teniposide improved outcomes for higher risk patients. Intermediate dose mercaptopurine (1 g/m2) failed to improve outcomes for either group. 10-year EFS for patients with T-cell ALL, POG 8704 and 9404, were 49.1 ± 3.1% and 72.2 ± 4.7%, respectively. Intensive asparaginase (10-year EFS 61.8% vs 42.7%) and high dose MTX (5 g/m2) (10-year EFS 78.0% vs. 65.8%) improved outcomes. There was a non-significant improvement in EFS for infants (10-year EFS 17.7 ± 7.2% to 31.9 ± 8.3%). Prognostic indicators for B-precursor ALL were age and WBC at diagnosis, gender, central nervous system disease, DNA index, and cytogenetic abnormalities. Only gender was prognostic in T-cell ALL. In infants, WBC and MLL translocation were linked to inferior outcome.
doi:10.1038/leu.2009.261
PMCID: PMC4300959  PMID: 20016527
B-lineage ALL; T-lineage ALL; Infant ALL; Prognostic factors; Outcome
3.  Family Life Events in the First Year of Acute Lymphoblastic Leukemia Therapy: A Children’s Oncology Group Report 
Pediatric blood & cancer  2014;61(12):2277-2284.
Background
Despite higher cure rates, childhood acute lymphoblastic leukemia (ALL) may continue to result in considerable family strain. We sought to (i) measure incidence of divorce, reduced career opportunities, changes to work hours, home relocation, and changes to family planning at one year after ALL diagnosis; and (ii) Identify family and patient factors associated with these events.
Procedure
We conducted a prospective cohort study of 159 children with average risk-ALL enrolled and treated on COG protocol AALL0331 at 31 selected sites. Eligibility criteria included age ≥2 years and English or Spanish comprehension. Parents completed surveys at three time points during the first 12 months of therapy.
Results
Parents were at significantly increased risk of loss of employment (46% vs. 9.1%, P≤0.001) than peers nationally. 13% divorced/separated, 27% relocated homes, 22% decided not to have more children, 51% declined occupational opportunities, and 68% decreased work hours. In adjusted analyses, relocation correlated with less maternal education (OR: 4.27 [95% CI: 1.43–12.82]). Declining parental opportunities associated with family income <$50,000 (OR: 4.25 [95% CI: 1.50–12.02]) and child <5 years old (OR: 4.21 [95% CI: 1.73–10.25]). Deciding not to have more children correlated with smaller family size 2–3 versus 4–5 (OR: 3.62 [95% CI: 1.10–11.96]).
Conclusion
Families experience a high incidence of major life changes in the first year of ALL treatment. Understanding these burdens helps health care providers to provide appropriate anticipatory guidance and support. No unifying factor was associated with the different family events. Ongoing follow-up is planned to measure long-term outcomes.
doi:10.1002/pbc.25195
PMCID: PMC4282930  PMID: 25175168
family coping/functioning; leukemia; pediatric cancer
4.  Children’s Oncology Group’s 2013 Blueprint for Research: Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2012;60(6):957-963.
Approximately 90% of the 2,000 children, adolescents, and young adults enrolled each year in Children’s Oncology Group acute lymphoblastic leukemia (ALL) trials will be cured. However, high-risk subsets with significantly inferior survival remain, including infants, newly diagnosed patients with age ≥10 years, white blood count ≥50,000/µl, poor early response or T-cell ALL, and relapsed ALL patients. Effective strategies to improve survival include better risk stratification, optimizing standard chemotherapy and combining targeted therapies with cytotoxic chemotherapy, the latter of which is dependent upon identification of key driver mutations present in ALL.
doi:10.1002/pbc.24420
PMCID: PMC4045498  PMID: 23255467
acute lymphoblastic leukemia (ALL); COG ALL trials
5.  Improved Survival for Children and Adolescents With Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2012;30(14):1663-1669.
Purpose
To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's Oncology Group (COG) clinical trials between 1990 and 2005.
Patients and Methods
In total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5- and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death.
Results
Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased.
Conclusion
This study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.
doi:10.1200/JCO.2011.37.8018
PMCID: PMC3383113  PMID: 22412151
6.  Wnt Inhibition Leads to Improved Chemosensitivity in Pediatric Acute Lymphoblastic Leukemia 
British journal of haematology  2014;167(1):87-99.
Summary
While childhood acute lymphoblastic leukemia (ALL) is now highly curable, the dismal prognosis for children who relapse warrants novel therapeutic approaches. Previously, using an integrated genomic analysis of matched diagnosis - relapse paired samples, we identified overactivation of the Wnt pathway as a possible mechanism of recurrence. To validate these findings and document whether Wnt inhibition may sensitize cells to chemotherapy, we analyzed the expression of Activated β-catenin (and its downstream target BIRC5) using multiparameter phosphoflow cytometry and tested the efficacy of a recently developed Wnt inhibitor, iCRT14, in ALL cell lines and patient samples. We observed increased activation of β-catenin at relapse in 6 /10 patients. Furthermore, treatment of leukemic cell lines with iCRT14 led to significant downregulation of Wnt target genes and combination with traditional chemotherapeutic drugs resulted in a synergistic decrease in viability as well as a significant increase in apoptotic cell death. Finally, pre-treatment of purified blasts from patients with relapsed leukemia with the Wnt inhibitor followed by exposure to prednisolone, restored chemosensitivity in these cells. Our results demonstrate that overactivation of the Wnt pathway may contribute to chemoresistance in relapsed childhood ALL and that Wnt-inhibition may be a promising therapeutic approach.
doi:10.1111/bjh.13011
PMCID: PMC4207443  PMID: 24995804
acute lymphoblastic leukemia; phosphoflow cytometry; Wnt inhibition; chemosensitivity; relapse
7.  Current Concepts in Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia 
The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR–ABL1 fusion gene encoding for a chimeric BCR–ABL1 protein. It is present in 3–4% of pediatric acute lymphoblastic leukemia (Ph+ ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph+ ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph+ ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph+ ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph+ ALL expanded exponentially through careful mapping of pathways downstream of BCR–ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph+ ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph+ ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph+ ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias.
doi:10.3389/fonc.2014.00054
PMCID: PMC3971203  PMID: 24724051
acute lymphoblastic leukemia; BCR–ABL1; tyrosine kinase inhibition; chemotherapy; hematopoietic stem-cell transplantation
8.  Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia 
Cancer cell  2012;22(2):153-166.
SUMMARY
Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL, and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2 negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.
doi:10.1016/j.ccr.2012.06.005
PMCID: PMC3422513  PMID: 22897847
9.  Pilot Study of Nelarabine in Combination With Intensive Chemotherapy in High-Risk T-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2012;30(22):2753-2759.
Purpose
Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86–based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).
Patients and Methods
In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; ≥ 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m2 once per day; four patients with SER by high minimal residual disease (MRD; ≥ 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m2 once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m2 once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]).
Results
The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16).
Conclusion
Addition of nelarabine to a BFM 86–based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly.
doi:10.1200/JCO.2011.40.8724
PMCID: PMC3402886  PMID: 22734022
10.  Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles 
Leukemia  2011;25(10):1555-1563.
Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-Down syndrome (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression, and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only two NDS cases (3.1%) (Fisher’s exact p = 0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters, and enrichment of highly methylated genes for specific pathways and transcription factor binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.
doi:10.1038/leu.2011.128
PMCID: PMC4107887  PMID: 21647151
Down syndrome; acute lymphoblastic leukemia (ALL); histone; JAK2; CRLF2
11.  Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse 
Nature genetics  2013;45(12):1494-1498.
Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a novel high-risk subtype with a gene expression signature resembling Philadelphia chromosome-positive ALL and a poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a single susceptibility locus for Ph-like ALL (GATA3, rs3824662, P=2.17×10−14, odds ratio [OR]=3.85, for Ph-like ALL vs. non-ALL; P=1.05×10−8, OR=3.25, for Ph-like ALL vs. non-Ph-like ALL) that was independently validated. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (i.e., CRLF2 rearrangement, JAK mutation, and IKZF1 deletion) and directly influenced GATA3 transcription. Finally, GATA3 SNP genotype was also associated with early treatment response and the risk of ALL relapse. Our results provide insights into interactions between host and tumor genomes and their importance in ALL pathogenesis and prognosis.
doi:10.1038/ng.2803
PMCID: PMC4039076  PMID: 24141364
12.  Novel Susceptibility Variants at 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethnically Diverse Populations 
Background
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the incidence of ALL varies by ethnicity. Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined.
Methods
We performed a multiethnic genome-wide association study in 1605 children with ALL and 6661 control subjects after adjusting for population structure, with validation in three replication series of 845 case subjects and 4316 control subjects. Association was tested by two-sided logistic regression.
Results
A novel ALL susceptibility locus at 10p12.31-12.2 (BMI1-PIP4K2A, rs7088318, P = 1.1×10−11) was identified in the genome-wide association study, with independent replication in European Americans, African Americans, and Hispanic Americans (P = .001, .009, and .04, respectively). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. Associations at ARID5B, IKZF1, and BMI1-PIP4K2A variants were consistent across ethnicity, with multiple independent signals at IKZF1 and BMI1-PIP4K2A loci. The frequency of ARID5B and BMI1-PIP4K2A variants differed by ethnicity, in parallel with ethnic differences in ALL incidence. Suggestive evidence for modifying effects of age on genetic predisposition to ALL was also observed. ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at a ninefold (95% confidence interval = 6.9 to 11.8) higher ALL risk relative to those carrying zero to one risk allele at these four single nucleotide polymorphisms.
Conclusions
These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children and shed new light on ALL molecular etiology in diverse ancestry.
doi:10.1093/jnci/djt042
PMCID: PMC3691938  PMID: 23512250
13.  THE GENOMIC LANDSCAPE OF HYPODIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA 
Nature genetics  2013;45(3):242-252.
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
doi:10.1038/ng.2532
PMCID: PMC3919793  PMID: 23334668
14.  A Multi-Center Phase Ib Study of Oxaliplatin (NSC#266046) in Combination with Fluorouracil and Leucovorin in Pediatric Patients with Advanced Solid Tumors 
Pediatric blood & cancer  2012;60(2):230-236.
Background
Platinum agents have been used for a variety of cancers, including pivotal use in pediatric tumors for many years. Oxaliplatin, a third generation platinum, has a different side effect profile and may provide improved activity in pediatric cancers.
Procedure
Patients 21 years or younger with progressive or refractory malignant solid tumors, including tumors of the central nervous system were enrolled on this multi-center open label, non-randomized phase 1 dose escalation study. The study used a standard 3+3 dose escalation design with 2 dose levels (85 mg/m2 and 100 mg/m2) with an expansion cohort of 15 additional patients at the recommended dose. Patients received oxaliplatin at the assigned dose level and 5-fluorouracil bolus 400 mg/m2 followed by a 46-hour 5-fluorouracil infusion of 2,400 mg/m2 every 14 days. The leucovorin dose was fixed at 400 mg/m2 for all cohorts.
Results
Thirty-one evaluable patients were enrolled, 8 at 85 mg/m2 and 23 at 100 mg/m2 for a total of 121 courses. The median age was 12 years (range 2–19 years). The main toxicities were hematologic, primarily neutrophils and platelets. The most common non-hematologic toxicities were gastrointestinal. Stable disease was noted in 11 patients (54% of evaluable patients) and 1 confirmed partial response in a patient with osteosarcoma.
Conclusions
The maximum planned dose of oxaliplatin at 100 mg/m2 per dose in combination with 5-fluorouracil and leucovorin was safe and well tolerated and in this patient population. This combination demonstrated modest activity in patients with refractory or relapsed solid tumor and warrants further study.
doi:10.1002/pbc.24278
PMCID: PMC3522763  PMID: 23024067
oxaliplatin; pediatrics; chemotherapy; 5-Fluorouracil; FOLFOX; phase I
15.  Acute Lymphoblastic Leukemia (ALL) with t(8;14)(q11.2;q32): B-cell disease with high proportion of Down Syndrome. A Children's Oncology Group (COG) Study 
Cancer genetics  2012;205(9):453-458.
The rare translocation t(8;14)(q11.2;q32) has been described in patients with B-cell acute lymphoblastic leukemia (ALL), particularly patients with Down Syndrome (DS).
We describe patients with t(8;14)(q11.2;q32) that were identified by the Children's Oncology Group (COG) ALL cytogenetics database, expanding our previous report of 10 patients with this translocation. Twenty-two such patients were treated with COG protocols. All patients had B-cell ALL and 7 (31.8%) had DS. None of the children with DS had an event, thus these patients had a superior estimated 5-year event-free survival (EFS) compared to non-DS patients (100% vs. 50.1 ± 17.7%; p=0.04). Only one patient (4.5%) had a concomitant Philadelphia chromosome t(9;22)(q34;q11.2). The cytogenetics data of two additional patients, who were not eligible for COG protocols, are also included in this report.
In conclusion, ALL patients with the recurring translocation t(8;14)(q11.2;q32) have B-cell phenotype and a high percentage have DS. Children with DS and t(8;14)(q11.2;q34) have improved event-free survival using standard COG therapy compared to non-DS patients. We did not find an increased number of patients with a concomitant Philadelphia chromosome in this population.
doi:10.1016/j.cancergen.2012.07.016
PMCID: PMC3432955  PMID: 22939398
Acute Lymphoblastic Leukemia; B-cell; translocation; Down Syndrome
16.  Alternate-Week versus Continuous Dexamethasone Scheduling on the Risk of Osteonecrosis in Acute Lymphoblastic Leukemia: Results from the CCG-1961 Randomized Cohort Trial 
The lancet oncology  2012;13(9):906-915.
SUMMARY
Background
Acute lymphoblastic leukemia (ALL) is curable in over 80% of children and adolescents with high-risk features. However, current therapies are associated with symptomatic osteonecrosis that disproportionately affects adolescents, often requires surgery, and is one of the most common causes of short- and long-term morbidity. A strategy is needed to lessen this risk.
Methods
CCG-1961, a multi-cohort randomized cooperative group trial, evaluated components of therapeutic intensification in 2056 eligible, newly diagnosed high-risk patients (white blood cell count ≥50×109/L and/or age ≥10 years). To address osteonecrosis, a novel alternate-week dexamethasone schedule (10 mg/m2/day on days 0-6 and 14-20) was compared to standard continuous dexamethasone (10 mg/m2/day on days 0-20) in randomized regimens with either double or single delayed intensification phases, respectively. Randomization was done based on a randomization schedule generated using permuted blocks within strata. Patients were prospectively monitored clinically for osteonecrosis, with confirmatory imaging of suspected sites. Primary analyses were performed on an intent-to-treat basis and focused on the estimation and comparison of cumulative incidence rates of osteonecrosis both overall and in patient subgroups (age, gender, marrow early response status); final results are herein reported. This study is registered with ClinicalTrials.gov, number NCT00002812.
Findings
Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. The overall cumulative incidence of osteonecrosis was 7·7% (N=2056) at 5 years, correlating with age at ALL diagnosis (1-9 years 1·0% (N=769), 10-15 years 9·9% (N=1025), ≥16 years 20·0% (N=262), p<0·0001) and gender (≥10 years, female 15·7% (N=525) versus male 9·3% (N=762), p=0·0010). For patients ≥10 years old with a rapid response to induction therapy, the use of alternate-week dexamethasone during delayed intensification phases significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7±2·1% (N=420) versus 17·0±2·9% (N=403), p=0·0005), especially those ≥16 years (11·3±5·3% (N=84) versus 37·5±11·1% (N=79), p=0·0003; females 17·2±8·1% (N=32) versus 43·9±14·1% (N=23), p=0·050; males 7·7±5·9% (N=53) versus 34·6±11·6% (N=56), p=0·0014).
Interpretation
Alternate-week dexamethasone during delayed intensification phases effectively reduces osteonecrosis risk in children and adolescents receiving intensified therapy for high-risk ALL.
doi:10.1016/S1470-2045(12)70274-7
PMCID: PMC3448283  PMID: 22901620
17.  Relapse specific mutations in NT5C2 in childhood acute lymphoblastic leukemia 
Nature genetics  2013;45(3):290-294.
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis despite intensive retreatment, due to intrinsic drug resistance1-2. The biological pathways that mediate resistance are unknown. Here we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten pediatric B lymphoblastic leukemia patients using RNA-sequencing. Transcriptome sequencing identified 20 newly acquired novel non-synonymous mutations not present at initial diagnosis, of which two patients harbored relapse specific mutations in the same gene, NT5C2, a 5′-nucleotidase. Full exon sequencing of NT5C2 was completed in 61 additional relapse specimens, identifying five additional cases. Enzymatic analysis of mutant proteins revealed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analogue therapies. Clinically, all patients who harbored NT5C2 mutations relapsed early, or within 36 months of initial diagnosis (p=0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug resistant clones in ALL.
doi:10.1038/ng.2558
PMCID: PMC3681285  PMID: 23377183
18.  Lessons Learned From The Investigational Device Exemption (IDE) Review of Children's Oncology Group Trial AAML1031 
Clinical Cancer Research  2012;18(6):1547-1554.
The FDA is now exerting its regulatory authority over molecular diagnostics and their assays used for medical-decision making in clinical trials by performing pre-Investigational Device Exemption (IDE) reviews in all phases of clinical trials. This review assesses the analytical performance of the assay for the diagnostic and considers how that performance affects the diagnostic and the patient and their risks and benefits from treatment. This manuscript reviews the process of the first review that was performed on a new Children's Oncology Group (COG) Phase III trial in Acute Myelogenous Leukemia. The lessons learned and recommendations for how to prepare for and incorporate this new level of regulatory review into the protocol development process are presented.
doi:10.1158/1078-0432.CCR-11-2205
PMCID: PMC3310885  PMID: 22422407
19.  ARID5B Genetic Polymorphisms Contribute to Racial Disparities in the Incidence and Treatment Outcome of Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2012;30(7):751-757.
Purpose
Recent genome-wide screens have identified genetic variations in ARID5B associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). We sought to determine the contribution of ARID5B single nucleotide polymorphisms (SNPs) to racial disparities in ALL susceptibility and treatment outcome.
Patients and Methods
We compared the association between ARID5B SNP genotype and ALL susceptibility in whites (> 95% European genetic ancestry; 978 cases and 1,046 controls) versus in Hispanics (> 10% Native American ancestry; 330 cases and 541 controls). We determined the relationships between ARID5B SNP genotype and ALL relapse risk in 1,605 children treated on the Children's Oncology Group (COG) P9904/9905 clinical trials.
Results
Among 49 ARID5B SNPs interrogated, 10 were significantly associated with ALL susceptibility in both whites and Hispanics (P < .05), with risk alleles consistently more frequent in Hispanics than in whites. rs10821936 exhibited the most significant association in both races (P = 8.4 × 10−20 in whites; P = 1 × 10−6 in Hispanics), and genotype at this SNP was highly correlated with local Native American genetic ancestry (P = 1.8 × 10−8). Multivariate analyses in Hispanics identified an additional SNP associated with ALL susceptibility independent of rs10821936. Eight ARID5B SNPs were associated with both ALL susceptibility and relapse hazard; the alleles related to higher ALL incidence were always linked to poorer treatment outcome and were more frequent in Hispanics.
Conclusion
ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.
doi:10.1200/JCO.2011.38.0345
PMCID: PMC3295551  PMID: 22291082
20.  The Controversy of Varicella Vaccination in Children with Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2010;58(1):12-16.
Background
The available guidelines for varicella vaccination of susceptible children with acute lymphoblastic leukemia (ALL) have become increasingly conservative. However, vaccination of those who have remained in continuous complete remission for one year and are receiving chemotherapy is still considered a reasonable option. There is little available data to allow a comparison of the risk vs. benefit of vaccinating these patients.
Procedure
We retrospectively reviewed mortality due to varicella in the records of 15 pediatric ALL study groups throughout Europe, Asia, and North America during the period 1984–2008.
Results
We found that 20 of 35,128 children with ALL (0.057%; 95% confidence interval [CI], 0.037%–0.088%) died of VZV infection. The mortality rate was lower in North America (3 of 11,558 children, 0.026%; 95% CI, 0.009%–0.076%) than in the Asian countries (2 of 4,882 children, 0.041%; 95% CI, 0.011%–0.149%) and in Europe (15 of 18,688 children, 0.080%; 95% CI, 0.049%–0.132%) consistent with the generally higher rate of VZV vaccination in North America. Fourteen of the 20 patients (70%) died during the first year of treatment for ALL. One death was attributed to varicella vaccination.
Conclusions
The negligible rate of fatal varicella infection in children with ALL, the risk that accompanies vaccination, and the necessity of withholding chemotherapy for vaccination appear to outweigh the potential benefit of varicella vaccination for children during treatment of ALL.
doi:10.1002/pbc.22759
PMCID: PMC3004985  PMID: 20848637
varicella zoster virus; pediatric; acute lymphoblastic leukemia; vaccination; immunization; mortality
21.  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
22.  Augmented Therapy Improves Outcome For Pediatric High Risk Acute Lymphocytic Leukemia: Results Of Children’s Oncology Group Trial P9906 
Pediatric blood & cancer  2011;57(4):569-577.
Background
The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.
Procedures
Children’s Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of Induction and correlated with outcome.
Results
The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ±3.7% versus 50.6 ±2.4%; p=0.0007) but similar to POG 9406 (63.5±2.4%; p=0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥100,000/microliter. Day 29 marrow MRD positive (>=0.01%) vs. negative patients had 5 year CCR rates of 37.1±7.4% vs. 72.6±4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ±4.6 % vs.83.6±6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD>0.01%, initial WBC≥100,000/µl, male gender, and day 8 blood MRD>0.01% were significant prognostic factors.
Conclusions
Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients.
doi:10.1002/pbc.22944
PMCID: PMC3136564  PMID: 21360654
Acute lymphocytic leukemia; Phase III clinical trial; Prognostic factors; Minimal residual disease
23.  Pediatric T-Cell Post-Transplant Lymphoproliferative Disorder After Solid Organ Transplantation 
Pediatric blood & cancer  2008;50(2):415-418.
Post-transplant lymphoproliferative disorder (PTLD) is the most after SOT (liver and lungs) and review cases reported in the literature. common treatment related malignancy that occurs after solid organ Both patients had a bimodal response to therapy with initial transplantation (SOT). PTLD has extended from its initial description eradication of bulky nodal disease with regimens typically used to as an Epstein–Barr virus (EBV)-driven B-cell proliferation to include treat leukemia, but persistence of low-level clonal T-cells in marrow, EBV-negative and non B-lineage cases. T-cell PTLD (T-PTLD) is rare CSF and lung in one case. Pediatr Blood Cancer 2008;50:415–in both adults and children. We report two cases of pediatric T-PTLD 418.
doi:10.1002/pbc.21072
PMCID: PMC3419753  PMID: 17051534
flow cytometry; T-cell PTLD; T-cell receptor V-beta
24.  The genetic basis of early T-cell precursor acute lymphoblastic leukaemia 
Nature  2012;481(7380):157-163.
Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.
doi:10.1038/nature10725
PMCID: PMC3267575  PMID: 22237106

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