Plasma steady state methotrexate (MTX) level and red blood cell (RBC) MTX and folate concentrations were evaluated in 1124 children with newly diagnosed acute lymphoblastic leukemia (ALL) enrolled on the Pediatric Oncology Group studies 9005 (lower risk; Regimens A and C) and 9006 (higher risk; Regimen A). These regimens included intermediate dose MTX (1 gram/m2) given as a 24 hour infusion every other week for 12 doses during intensification. Plasma MTX level was evaluated at the end of MTX infusions. RBC MTX and folate concentrations were measured at the end of intensification. The five year continuous complete remission (CCR) was 76 ± 1.4% versus 85 ± 3.0% for those patients with steady state MTX levels ≤ and > 14 µM, respectively (p=0.0125). Hispanic children had significantly reduced median steady state MTX levels, 8.7 µM, compared to non-Hispanic children, 9.95 µM (p=0.0015), but this did not correlate with a difference in outcome. Neither RBC MTX, RBC folate, nor the RBC MTX:folate ratio identified children at increased risk of failure.
Red Blood Cell Methotrexate and Folate; Childhood Acute Lymphoblastic Leukemia
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.
Acute Lymphoblastic Leukemia; B-cell; translocation; Down Syndrome
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.
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.
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).
Alternate-week dexamethasone during delayed intensification phases effectively reduces osteonecrosis risk in children and adolescents receiving intensified therapy for high-risk ALL.
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.
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]).
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).
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.
Despite efforts to intensify chemotherapy, survival for patients with metastatic osteosarcoma remains poor. Overexpression of human epidermal growth factor receptor 2 (HER2) in osteosarcoma has been shown to predict poor therapeutic response and decreased survival. This study tests the safety and feasibility of delivering biologically targeted therapy by combining trastuzumab with standard chemotherapy in patients with metastatic osteosarcoma and HER2 overexpression.
Patients and Methods
Among 96 evaluable patients with newly diagnosed metastatic osteosarcoma, 41 had tumors that were HER2-positive by immunohistochemistry. All patients received chemotherapy with cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide. Dexrazoxane was administered with doxorubicin to minimize the risk of cardiotoxicity from treatment with trastuzumab and anthracycline. Only patients with HER2 overexpression received concurrent therapy with trastuzumab given for 34 consecutive weeks.
The 30-month event-free and overall survival rates for patients with HER2 overexpression treated with chemotherapy and trastuzumab were 32% and 59%, respectively. For patients without HER2 overexpression, treated with chemotherapy alone, the 30-month event-free and overall survival rates were 32% and 50%, respectively. There was no clinically significant short-term cardiotoxicity in patients treated with trastuzumab and doxorubicin.
Despite intensive chemotherapy plus trastuzumab for patients with HER2-positive disease, the outcome for all patients was poor, with no significant difference between the HER2-positive and HER2-negative groups. Although our findings suggest that trastuzumab can be safely delivered in combination with anthracycline-based chemotherapy and dexrazoxane, its therapeutic benefit remains uncertain. Definitive assessment of trastuzumab's potential role in treating osteosarcoma would require a randomized study of patients with HER2-positive disease.
Recent studies suggest that polymorphisms in genes encoding enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine polymorphic variants of genes and relapse risk, toxicity, and drug dose delivery in standard risk ALL.
We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the Children’s Cancer Group ALL study, CCG-1891. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individually and clique-finding methodology was employed for detection of significant gene-gene interactions.
After controlling for known risk factors, polymorphisms in four genes: GSTP1*B (HR=1.94, p=0.047), MTHFR (HR=1.61, p=0.034), MTRR (HR=1.95, p=0.01), and TS (3R/4R, HR=3.69, p=0.007), were found to significantly increase relapse risk. One gene-gene pair, MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse after correction for multiple comparisons (p=0.012). Multiple polymorphisms were associated with various toxicities and there was no significant difference in dose of chemotherapy delivered by genotypes.
These data suggest that various polymorphisms play a role in relapse risk and toxicity during childhood ALL therapy and that genotype does not play a role in adjustment of drug dose administered. Additionally, gene-gene interactions may increase the risk of relapse in childhood ALL and the clique method may have utility in further exploring these interactions. childhood ALL therapy.
genotype; acute lymphoblastic leukemia; prognosis; toxicity; gene-gene interactions
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.
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.
ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.
Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with initially unresected tumours represent a particular subset of patients with a poor outcome. Various international research groups pooled their data in a joint study in order to investigate prognostic variables and treatment modalities.
The study population consisted of 304 patients <21 years old treated between 1980 and 2005 using a multimodality therapeutic strategy.
Synovial sarcoma and malignant peripheral nerve sheath tumour (MPNST) were the most frequent histotypes. Most patients received initial chemotherapy: major responses were recorded in 41% and minor in 16% of cases. Overall survival (OS) was 60.0% and 51.5% at 5 and 10 years, respectively, and it was significantly associated with patient's age, histological subtype, tumour site and size, quality of delayed surgical resection, radiotherapy administration and response to induction chemotherapy. MPNST associated to neurofibromatosis type 1 was the tumour type with the worst rate of response to chemotherapy and the worst outcome.
In unresected NRSTS patients, radiotherapy and delayed surgery are of crucial importance. Patients who respond to chemotherapy have better chance of survival. However, given the relatively poor prognosis, research on intensive multimodal treatment approaches and novel strategies is warranted.
Non-rhabdomyosarcoma soft tissue sarcomas; Unresected sarcoma; Paediatric sarcoma; Synovial sarcoma, malignant peripheral nerve sheath tumour; Chemotherapy, response to chemotherapy; Radiotherapy; Surgery; Prognostic factors
Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).
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.
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.
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.)
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.
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.
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.
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.
Acute lymphocytic leukemia; Phase III clinical trial; Prognostic factors; Minimal residual disease
Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with current therapy, the event-free survival (EFS) of infants with ALL, particularly those with mixed lineage leukemia (MLL) gene rearrangements, is only 30% to 40%. Relapse has been the major source of treatment failure for these patients. The parallel Children's Cancer Group (CCG) 1953 and Pediatric Oncology Group (POG) 9407 studies were designed to test the hypothesis that more intensive therapy, including dose intensification of chemotherapy, and hematopoietic stem-cell transplantation (HSCT) would improve the outcome for this group of patients.
Patients and Methods
One hundred eighty-nine infants (CCG 1953, n = 115; POG 9407, n = 74) were enrolled between October 1996 and August 2000. For infants with the MLL gene rearrangement and an appropriate donor, HSCT was the preferred treatment on CCG 1953 and investigator option on POG 9407 after completion of the second phase of therapy. Fifty-three infants underwent HSCT.
The 5-year EFS rate was 48.8% (95% CI, 33.9% to 63.7%) in patients who received HSCT and 48.7% (95% CI, 33.8% to 63.6%) in patients treated with chemotherapy alone (P = .60). Transplantation outcomes were not affected by the preparatory regimen or donor source.
Our data suggest that routine use of HSCT for infants with MLL-rearranged ALL is not indicated. However, limited by small numbers, this study should not be considered the definitive answer to this question.
Acute Lymphoblastic Leukemia (ALL) non-random fusions influence clinical outcome and alter the accumulation of MTX-PGs in vivo. Analysis of primary ALL samples uncovered subtype-specific patterns of folate gene expression. Using an FPGS-luciferase reporter gene assay, we determined that E2A-PBX1 and TEL-AML1 expression decreased FPGS transcription. ChIP assays uncovered HDAC1,AML1, mSin3A, E2F, and Rb interactions with the FPGS promoter region. We demonstrate that FPGS expression is epigenetically regulated through binding of selected ALL fusions to a multiprotein complex, which also controls the cell cycle dependence of FPGS expression. This study provides insights into the pharmacogenomics of MTX in ALL subtypes.
FPGS; TEL-AML1; Rb/E2F; Chromatin remodeling; ALL; leukemia; HDAC1; methotrexate
The Children’s Oncology Group (COG) is a National Cancer Institute sponsored cooperative clinical trials group with the primary mission of conducting pediatric cancer clinical trials. COG has complex risk classification systems that are used to deliver risk-stratified therapy for many pediatric cances, including clinical trials for Acute Lymphoblastic Leukemia (ALL) and Neuroblastoma (NB). Classification of patients is based on biological, clinical, and genomic data obtained at initial diagnosis and during the initial phases of therapy. The COG web-based remote data entry (RDE) system enables submission of data in real time from central laboratories and treating institutions. The data are then used in an automated fashion to determine the risk group and corresponding treatment assignment for individual patients enrolled in COG clinical trials.
Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups.
Patients and Methods
We evaluated whether imatinib (340 mg/m2/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph− ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) –identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT.
Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% ± 11% (95% CI, 64% to 90%), more than twice historical controls (35% ± 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% ± 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% ± 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction.
Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.
Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002.
Patients and Methods
CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count ≥ 50,000/μL and/or age ≥ 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL.
Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/μL was an adverse prognostic factor.
Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.
The Children’s Cancer Group enrolled 13,298 young people age < 21 years on one of 16 protocols between 1983 and 2002. Outcomes were examined in three time periods, 1983–1988, 1989–1995, 1996–2002. Over the three intervals, 10-year event-free survival (EFS) for Rome/NCI standard risk and higher risk B-precursor patients was 68% and 58%, 77% and 63%, and 78% and 67%, respectively; while for standard risk and higher risk T-cell patients, EFS was 65% and 56%, 78% and 68%, and 70% and 72%, respectively. Five-year EFS for infants was 36%, 38%, and 43%, respectively. Seminal randomized studies led to a number of important findings. Stronger post induction intensification improved outcome for both standard and higher risk patients. With improved systemic therapy, additional IT methotrexate effectively replaced cranial radiation. For standard risk patients receiving three-drug induction, iso-toxic substitution of dexamethasone for prednisone improved EFS. Pegylated asparaginase safely and effectively replaced native asparaginase. Thus, rational therapy modifications yielded better outcomes for both standard and higher risk patients. These trials provide the platforms for current Children’s Oncology Group trials.
Acute lymphoblastic leukemia; children; randomized clinical trials
The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.
Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks.
Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites.
Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.
Despite great progress in curing childhood acute lymphoblastic leukemia, survival after relapse remains poor. We analyzed survival following relapse among 9,585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988-2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary endpoint was survival. Patients were subcategorized by site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0±1.8%. Standard risk patients who relapsed had improved survival compared to their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10+ yrs) and presence of CNS disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. Of note, there was no difference in survival rates for relapsed patients in earlier versus later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance.
relapsed acute lymphoblastic leukemia; Children's Oncology Group; pediatric
We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1×10−5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4×10−15, odds ratio[OR]=1.91; rs10994982, P=5.7×10−9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 ×10−5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes.
Recurrent, prognostically significant chromosomal abnormalities occur in approximately 75% of pediatric acute lymphoblastic leukemia (ALL), but only infrequently in children with Down syndrome (DS) and ALL. Recently, novel somatic activating mutations in Janus kinase 2 (JAK2) were reported in 18% of DS ALL. Here we report identification and clinical correlates of JAK2 mutations in an independent cohort. JAK2 activating mutations occurred in 10 of 53 DS ALL cases (18.9%). Mutations were overrepresented in males (p<0.03), occurred once in association with high hyperdiploidy, and were not significantly correlated with age, initial white blood count, or event-free survival. Our results confirm significance of JAK-STAT pathway activation in DS ALL.
Down syndrome; pediatric; acute lymphoblastic leukemia; JAK2
We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. In T-ALL lymphoblasts, we identified high frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3-3.3-fold increased transactivation of a HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1, cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltranserase, Bcl-2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.
acute lymphoblastic leukemia; NOTCH1; FBW7; PTEN; HES1; DELTEX1; cMYC; chemotherapy; T-cell
Treatment of childhood relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. The goal of the Children's Oncology Group (COG) AALL01P2 study was to develop a safe and active chemotherapy reinduction platform, which could be used to evaluate novel agents in future trials.
Patients and Methods
One hundred twenty-four patients with ALL and first marrow relapse received three, 35-day blocks of reinduction chemotherapy: 69 with early relapse (ER; < 36 months from initial diagnosis) and 55 with late relapse (LR). Minimal residual disease (MRD) was measured by flow cytometry after each treatment block.
Second complete remission (CR2) rates at the end of block 1 in 117 assessable patients were 68% ± 6% for ER (n = 63) and 96% ± 3% for LR (n = 54; P < .0001). Five of seven patients with T-cell ALL (T-ALL) failed to achieve CR2. Among patients in CR2, MRD greater than 0.01% was detected at the end of block 1 in 75% ± 7% of ER (n = 36) versus 51% ± 8% of LR (n = 43; P = .0375) and 12-month event-free survival was 80% ± 7% versus 58% ± 7% in MRD-negative versus positive patients (P < .0005). Blocks 2 and 3 of therapy resulted in reduction of MRD burden in 40 of 56 patients who were MRD positive after block 1. Toxicity was acceptable during all three blocks with five deaths (4%) from infections.
The AALL01P2 regimen is a tolerable and active reinduction platform, suitable for testing in combination with novel agents in B-precursor ALL. Alternative strategies are needed for T-ALL. Serial MRD measurements were feasible and prognostic of outcome.
Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined.
We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL.
More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell–lineage genes, and it was similar to the signature of BCR-ABL1–positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.
Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell–progenitor ALL.