The delayed intensification (DI) enhanced outcome for patients with acute lymphoblastic leukemia (ALL) treated on BFM 76/79 and CCG 105 after a prednisone-based induction. Childrens Oncology Group protocols P9904/9905 evaluated DI via a post-induction randomization for eligible National Cancer Institute (NCI) standard (SR) and high-risk (HR) patients. A second randomization compared intravenous methotrexate (IV MTX) as a 24- (1 g/m2) vs. 4-h (2 g/m2) infusion. NCI SR patients received a dexamethasone-based three-drug and NCI HR/CNS 3 SR patients a prednisone-based four-drug induction. End induction MRD (minimal residual disease) was obtained but did not impact treatment. DI improved the 10-year continuous complete remission (CCR) rate; 75.5 ± 2.5% vs. 81.8 ± 2.2% p = 0.002, whereas MTX administration did not; 4-h 80.8 ± 1.9%; 24-h 81.4 ± 1.9% (p = 0.7780). Overall survival (OS) at 10 years did not differ with DI: 91.4 ± 1.6% vs. 90.9 ± 1.7% (p = 0.25) without but was higher with the 24-h MTX infusion; 4-h 91.1 ± 1.4%; 24-h 93.9 ± 1.2% (p = 0.0209). MRD predicted outcome; 10-year CCR 87.7 ± 2.2 and 82.1 ± 2.5% when MRD was <0.01% with/without DI (p = 0.007) and 54.3 ± 8% and 44 ± 8% for patients with MRD ≥ 0.01% with/without DI (p = 0.11). DI improved CCR for patients with B-ALL with and without end induction MRD.

PURPOSE:To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m(2) to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic non-Hodgkin lymphoma (L-NHL).PATIENTS AND METHODS:Patients were treated on Pediatric Oncology Group Protocol POG 9404, which included random assignment to treatment with or without dexrazoxane given as a bolus infusion immediately before every dose of doxorubicin. Cardiac effects were assessed by echocardiographic measurements of left ventricular function and structure.RESULTS:Of 573 enrolled patients, 537 were eligible, evaluable, and randomly assigned to an arm with or without dexrazoxane. The 5-year event-free survival (with standard error) did not differ between groups: 77.2% (2.7%) for the dexrazoxane group versus 76.0% (2.7%) for the doxorubicin-only group (P = .9). The frequencies of severe grade 3 or 4 hematologic toxicity, infection, CNS events, and toxic deaths were similar in both groups (P ranged from .26 to .64). Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 55 per group; P ≤ .01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (-2.03 v -0.24; P ≤ .001).CONCLUSION:Dexrazoxane was cardioprotective and did not compromise antitumor efficacy, did not increase the frequencies of toxicities, and was not associated with a significant increase in second malignancies with this doxorubicin-containing chemotherapy regimen. We recommend dexrazoxane as a cardioprotectant for children and adolescents who have malignancies treated with anthracyclines.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related death in children and adolescents. Minimal residual disease (MRD) is a strong, independent prognostic factor. The objective of this study was to identify molecular signatures distinguishing patients with positive MRD from those with negative MRD in different subtypes of ALL, and to identify molecular networks and biological pathways deregulated in response to positive MRD at day 46. We compared gene expression levels between patients with positive MRD and negative MRD in each subtype to identify differentially expressed genes. Hierarchical clustering was applied to determine their functional relationships. We identified subtype-specific gene signatures distinguishing patients with positive MRD from those with negative MRD. We identified the genes involved in cell cycle, apoptosis, transport, and DNA repair. We also identified molecular networks and biological pathways dysregulated in response to positive MRD, including Granzyme B, B-cell receptor, and PI3K signaling pathways.

BackgroundInfants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6–9 months of diagnosis is common. Approximately 75% of infants have MLL‐rearranged (MLL‐R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS.ProcedureP9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty‐seven infants were enrolled in the third cohort.ResultsWe report an overall 5‐year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL‐R ALL and white cell count ≥50,000/μl. For infants ≤90 days of age, the 5‐year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5‐year EFS rates were 43.8 ± 8% for MLL‐R versus 69.1 ± 13.6% for MLL‐germline ALL (P < 0.0001).ConclusionsAge ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL‐R ALL. Pediatr Blood Cancer 2015;62:419–426. © 2014 Wiley Periodicals, Inc.

Purpose: To determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate (MTX) and pulses of high-dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL).Patients and Methods: From 1994 to 1999, the Pediatric Oncology Group conducted a randomized phase III clinical trial in higher risk pediatric B-precursor ALL. A total of 784 patients were randomized in a 2 x 2 factorial design to receive MTX 1 g/m(2) versus 2.5 g/m(2) and to cytosine arabinoside/teniposide versus high-dose cytosine arabinoside/asparaginase during intensified continuation therapy.Results: Patients receiving standard dose MTX had a 5-year disease-free survival (DFS) of 71.8 +/- 2.4%; patients receiving higher dose MTX had a 5-year DFS of 71.7 +/- 2.4% (P = 0.55). Outcomes on cytosine arabinoside/teniposide (DFS of 70.4 +/- 2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1 +/- 2.3%) (P = 0.41). Overall survival rates were not different between MTX doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase.Conclusions: Increasing MTX dosing to 2.5 g/m(2) did not improve outcomes in higher risk pediatric B-precursor ALL. Giving high-dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant differences in outcomes, allowing for teniposide to be removed from ALL therapy.

As controversy exists regarding the prognostic significance of genomic rearrangements of CRLF2 in pediatric B-precursor acute lymphoblastic leukemia (ALL) classified as standard/intermediate-risk (SR) or high-risk (HR), we assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes frequently associated with high CRLF2 expression (IKZF1, JAK, IL7R), and minimal residual disease (MRD) in 1061 pediatric ALL patients (499 HR and 562 SR) on COG Trials P9905/P9906. Whereas very high CRLF2 expression was found in 17.5% of cases, only 51.4% of high CRLF2 expressors had CRLF2 genomic lesions. The mechanism underlying elevated CRLF2 expression in cases lacking known genomic lesions remains to be determined. All CRLF2 genomic lesions and virtually all JAK mutations were found in high CRLF2 expressors, whereas IKZF1 deletions/mutations were distributed across the full cohort. In multivariate analyses, NCI risk group, MRD, high CRLF2 expression, and IKZF1 lesions were associated with relapse-free survival. Within HR ALL, only MRD and CRLF2 expression predicted a poorer relapse-free survival; no difference was seen between cases with or without CRLF2 genomic lesions. Thus, high CRLF2 expression is associated with a very poor outcome in high-risk, but not standard-risk, ALL. This study is registered at www.clinicaltrials.gov as NCT00005596 and NCT00005603.

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 clay 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% vs. 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. clay 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, clay 29 MRD > 0.01%, initial WBC >= 100,000/mu l, 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. Pediatr Blood Cancer 2011;57:569-577. (C) 2011 Wiley-Liss, Inc.

9505 Background: We previously reported a highly significant association between over-expression of CRLF2 (cytokine receptor-like factor 2) and poor clinical outcomes in 207 uniformly-treated children with high-risk B-ALL (Blood 115:5312, 2010). To validate and extend these studies to standard risk cases we studied 896 B-ALL patients from COG P9905. Eligible patients included 344 with NCI high-risk (HR) features and 552 with standard-risk (SR) features. Methods: Quantitative RT-PCR assays were used to determine CRLF2 expression in the diagnostic leukemic cells. Averages of duplicate assays were used to establish ΔCt values relative to a control gene (EEF2). Using the ΔCt threshold determined from our prior studies, 117/896 B-ALL samples had elevated CRLF2 expression. These 117 samples and other 35 samples below the threshold were tested for genomic rearrangements of CRLF2 to detect the P2RY8-CRLF2 fusion or CRLF2 F232C mutations. Studies to detect the IGH@-CRLF2 translocation, IKZF1 (IKAROS) deletions, and JAK mutations are ongoing. Outcomes were evaluated using relapse-free survival (RFS) and other known risk factors. Results: CRLF2 overexpression was associated with a poorer outcome in HR, but not in SR, B-ALL. Among the 246 HR cases lacking detectable end-induction minimal residual disease, CRLF2 expression levels could further distinguish those B-ALL patients who had a very good (>80%) vs. poor (<40%) RFS (Hazard Ratio = 2.59; P=0.002). While P2RY8/CRLF2 fusions were seen only in high CRLF2-expressors, 6/17 CRLF2 F232C mutations were among low CRLF2 expressors. Down syndrome ALL cases had a relatively good outcome regardless of CRLF2 expression levels or NIH risk status. Conclusions: Elevated CRLF2 expression predicts a significantly poorer outcome in HR, but not SR, B-ALL and can be used with other prognostic factors to improve ALL risk classification. Standard-risk RFS High-risk RFS N Hazard ratio P N Hazard ratio P All cases (n=896) 552 – – 344 – – High CRLF2 81 1.20 .510 36 1.84 .019 Down syndrome (DS) 35 1.25 .571 5 0.94 .952 Genomic abnormalities 99 53 P2RY8 fusion 37 1.00 .988 14 1.64 .034 F232C mutation 15 – – 2 – –

The Pediatric Oncology Group (POG) phase 3 trial 9404 was designed to determine the effectiveness of high-dose methotrexate (HDM) when added to multi-agent chemotherapy based on the Dana-Farber backbone. Children with T-cell acute lymphoblastic leukemia (T-ALL) or advanced lymphoblastic lymphoma (T-NHL) were randomized at diagnosis to receive/not receive HDM (5 g/m² as a 24-hour infusion) at weeks 4, 7, 10, and 13. Between 1996 and 2000, 436 patients were enrolled in the methotrexate randomization. Five-year and 10-year event-free survival (EFS) was 80.2% ± 2.8% and 78.1% ± 4.3% for HDM (n = 219) versus 73.6% ± 3.1% and 72.6% ± 5.0% for no HDM (n = 217; P = .17). For T-ALL, 5-year and 10-year EFS was significantly better with HDM (n = 148, 5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%) versus no HDM (n = 151, 5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; P = .047). The difference in EFS between HDM and no HDM was not significant for T-NHL patients (n = 71, 5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5% vs n = 66, 5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; P = .38). The frequency of mucositis was significantly higher in patients treated with HDM (P = .003). The results support adding HDM to the treatment of children with T-ALL, but not with NHL, despite the increased risk of mucositis.

Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and an inferior outcome. We reviewed data from 2811 children with ALL enrolled in Children's Oncology Group P9900, which included prospective testing for the major cytogenetic lesions in childhood ALL: ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL translocations and trisomies of chromosomes 4 and 10. Eighty (3%) B-precursor ALL patients had DS. Age, sex, white blood cell count, and risk group were similar between DS-ALL and non-DS-ALL but significantly more patients with DS-ALL were white (91.2% vs 76.4%, P = .001). Children with DS-ALL had lower rates of the favorable cytogenetic lesions ETV6-RUNX1 (2.5% vs 24%, P < .001) and trisomies 4 and 10 (7.7% vs 24%, P < .001). Five-year event-free (EFS) and overall survival (OS) were inferior in children with DS-ALL: 69.9% +/- 8.6% versus 78.1% +/- 1.2% (P = .078), and 85.8% +/- 6.5% versus 90.0% +/- 0.9% (P = .033). However, when children with MLL translocations, BCR-ABL1, ETV6-RUNX1, and trisomies 4 and 10 were excluded, the EFS and OS were similar for children with and without DS (EFS 68.0 %+/- 9.3% vs 70.5% +/- 1.9%, P = .817; and OS 86.7% +/- 6.7% vs 85.4% +/- 1.5%; P = .852), both overall and adjusted for race. DS-ALL displays a unique spectrum of biologic subtypes with different frequencies of sentinel cytogenetic lesions having a large influence on outcome.

From 1984 to 2001, the Pediatric Oncology Group (POG) conducted 12 acute lymphoblastic leukemia (ALL) studies. Ten-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/m 2 ) 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/m 2 ) nor addition of cytosine arabinoside/daunomycin/teniposide improved outcomes for higher risk patients. Intermediate dose mercaptopurine (1 g/m 2 ) failed to improve outcomes for either group. Ten-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/m 2 ) (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±7.2–31.9±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.

PurposeTo prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia ( ALL).Patients and MethodsTEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years.ResultsRearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate ( +/- SE) for patients with TEL rearrangements was 86% +/- 2%, compared with 72% +/- 2% for those with germline TEL ( P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome ( P = .0002).ConclusionWe conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.

Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Insitute high-risk (NCI HR) patients who were MRD+. The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.

Bruce M. Camitta Elizabeth A. Raetz, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Paul S. Gaynon and Michael J. Borowitz, Andrew J. Carroll, Nyla A. Heerema, Jeffrey E. Rubnitz, Mignon L. Loh, Kirk R. Schultz, D. Jeanette Pullen, Harland N. Sather, Jonathan J. Shuster, Meenakshi Devidas, (CCG) from the Pediatric Oncology Group (POG) and Children's Cancer Group lymphoblastic leukemia: a combined analysis of prognostic markers Riskand response-based classification of childhood B-precursor acute

We describe the Outcome of children with B-precursor acute lymphoblastic leukemia registered on Pediatric Oncology Group 8602 who switched to Erwinia asparaginase (ASP) due to an allergy to the Escherichia coli product. Between February 1986 and January 1991, children in complete remission after induction that included intramuscular E. coli ASP (6000 U/m(2) x 6) were randomized for consolidation. One regimen included intensive weekly intramuscular E. coli ASP (25,000 U/m(2) /wk x 24). In case of an allergic reaction to E. coli ASP, Erwinia ASP was substituted at the same dose and schedule. Of the 540 eligible patients, 408 switched to Erwinia ASP due to an allergic reaction. Allergic reactions were significantly associated with younger age, white race, and standard-risk acute lymphoblastic leukemia. Multivariate Cox analysis adjusting for these factors demonstrated no correlation between the switch per se or the timing of the switch and event-free survival.

The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.