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1.
Leukemia ; 24(2): 285-97, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20016531

ABSTRACT

The Children's Cancer Group enrolled 13 298 young people age <21 years on 1 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/National Cancer Institute standard risk (SR) and higher risk (HR) B-precursor patients was 68 and 58%, 77 and 63%, and 78 and 67%, respectively, whereas for SR and HR 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 SR and HR patients. With improved systemic therapy, additional intrathecal (IT) methotrexate effectively replaced cranial radiation. For SR 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 SR and HR patients. These trials provide the platforms for current Children's Oncology Group trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cranial Irradiation , Neoplasm Recurrence, Local/therapy , Neoplasms, Second Primary/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Child , Child, Preschool , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Infant , Male , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasms, Second Primary/mortality , Neoplasms, Second Primary/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Remission Induction , Risk Factors , Survival Rate , Time Factors , Treatment Outcome
3.
Leukemia ; 19(5): 734-40, 2005 May.
Article in English | MEDLINE | ID: mdl-15789069

ABSTRACT

Chromosome aberrations have a major role in pediatric acute lymphoblastic leukemia (ALL) risk assignment. The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) independently assessed the significance of trisomy for chromosomes 4, 10, and 17 in National Cancer Institute (NCI) Standard- and High-Risk ALL. Data from 1582 (CCG) and 3902 (POG) patients were analyzed. Eight-year event-free survivals (EFS) of 91% (CCG) and 89% (POG) (P < 0.001) were achieved in patients assigned to NCI Standard Risk whose leukemic cells had simultaneous trisomies 4, 10, and 17. Both groups showed the degree of favorable prognostic importance increased with the actual number of favorable trisomies. POG analyses also demonstrated hyperdiploidy (> or =53 chromosomes) was less of an independently significant prognostic factor in the absence of these key trisomies. This finding supported conclusions from previous CCG and POG studies that specific trisomies are more important than chromosome number in predicting outcome in pediatric B-precursor ALL. In NCI Higher Risk patients, the number of favorable trisomies was not prognostically significant, but showed the same trend. Moreover, specific trisomies 4, 10, and 17 remain associated with favorable prognosis in Standard-Risk B-precursor ALL, even in the context of very different treatment approaches between the groups.


Subject(s)
Burkitt Lymphoma/genetics , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 4/genetics , Trisomy/genetics , Abnormalities, Multiple/genetics , Adolescent , Adult , Burkitt Lymphoma/diagnosis , Burkitt Lymphoma/immunology , Burkitt Lymphoma/mortality , Child , Child, Preschool , Chromosome Aberrations , Disease-Free Survival , Humans , Infant , National Institutes of Health (U.S.) , Prognosis , Reproducibility of Results , Risk Assessment , Risk Factors , Societies, Medical , Trisomy/diagnosis , United States
4.
Leukemia ; 18(4): 693-702, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15044926

ABSTRACT

Additional chromosomal aberrations occur frequently in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) of childhood. The treatment outcome of these patients is heterogeneous. This study assessed whether such clinical heterogeneity could be partially explained by the presence and characteristics of additional chromosomal abnormalities. Cytogenetic descriptions were available for 249 of 326 children with Ph+ ALL, diagnosed and treated by 10 different study groups/large single institutions from 1986 to 1996. Secondary aberrations were present in 61% of the cases. Chromosomes 9, 22, 7, 14, and 8 were most frequently abnormal. Most (93%) karyotypes were unbalanced. Three main cytogenetic subgroups were identified: no secondary aberrations, gain of a second Ph and/or >50 chromosomes, or loss of chromosome 7, 7p, and/or 9p, while other secondary aberrations were grouped as combinations of gain and loss or others. Of the three main cytogenetic subgroups, the loss group had the worst event-free survival (P=0.124) and disease-free survival (P=0.013). However, statistical significance was not maintained when adjusted for other prognostic factors and treatment. Karyotypic analysis is valuable in subsets of patients identified by molecular screening, to assess the role of additional chromosomal abnormalities and their correlation with clinical heterogeneity, with possible therapeutic implications.


Subject(s)
Chromosome Aberrations , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Chromosome Breakage , Chromosome Deletion , Cytogenetic Analysis , Disease-Free Survival , Female , Genetic Heterogeneity , Humans , Likelihood Functions , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Survival Analysis , Treatment Outcome
5.
Leukemia ; 18(4): 685-92, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14990973

ABSTRACT

Activating mutations in the RAS oncogenes are among the most common genetic alterations in human cancers, including patients with acute lymphoblastic leukemia (ALL). We sought to define the frequency and spectrum, and possible prognostic importance, of N- and K-RAS mutations in children with ALL treated with contemporary therapy. Leukemic blast DNA from 870 children was analyzed for the presence of activating mutations in the N- or K-RAS oncogenes using a sensitive mutation detection algorithm. RAS mutations were present in the blasts of 131 (15.1%) pediatric ALL patients. The spectrum of mutations included 81 (9.3%) mutations of codons 12/13 of N-RAS, 12 (1.4%) mutations of codon 61 of N-RAS, 39 (4.5%) mutations of codons 12/13 of K-RAS, and 2 (0.2%) mutations of codon 61 of K-RAS. The presence of N- or K-RAS mutations was not associated with white blood cell count at diagnosis, sex, race, extramedullary testicular involvement, central nervous system disease, or NCI/CTEP ALL Risk Group. Patients with an exon 1 K-RAS mutation (codons 12/13) were significantly younger at diagnosis (P=0.001) and less frequently B-lineage phenotype (P=0.01). RAS mutation status did not predict overall survival, event-free survival and disease-free survival. While N- and K-RAS mutations can be identified in 15% of children with newly diagnosed ALL, they do not represent a significant risk factor for outcome using contemporary chemotherapy regimens.


Subject(s)
Genes, ras/genetics , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , DNA Mutational Analysis , DNA, Neoplasm/genetics , Female , Humans , Infant , Infant, Newborn , Male , Molecular Epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Prognosis , Risk Factors , Survival Analysis , Treatment Outcome
6.
Leukemia ; 18(5): 939-47, 2004 May.
Article in English | MEDLINE | ID: mdl-14999294

ABSTRACT

Monosomy 7 or deletions of 7q are associated with many myeloid disorders; however, the significance of such abnormalities in childhood acute lymphoblastic leukemia (ALL) is unknown. Among 1880 children with ALL, 75 (4%) had losses involving chromosome 7, 16 (21%) with monosomy 7, 41 (55%) with losses of 7p (del(7p)), 16 (21%) with losses of 7q (del(7q)), and two (3%) with losses involving both arms. Patients with losses involving chromosome 7 were more likely to be > or =10 years old, National Cancer Institute (NCI) poor risk, and hypodiploid than patients lacking this abnormality. Patients with or without these abnormalities had similar early response to induction therapy. Event-free survival (EFS) and survival for patients with monosomy 7 (P<0.0001 and P=0.0007, respectively) or del(7p) (P<0.0001 and P=0.0001, respectively), but not of patients with del(7q), were significantly worse than those of patients lacking these abnormalities. The poorer EFS was maintained after adjustment for a Philadelphia (Ph) chromosome, NCI risk status, ploidy, or an abnormal 9p. However, the impact on survival was not maintained for monosomy 7 after adjustment for a Ph. These results indicate that the critical region of loss of chromosome 7 in pediatric ALL may be on the p-arm.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 7 , Monosomy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis
7.
Leukemia ; 17(5): 887-93, 2003 May.
Article in English | MEDLINE | ID: mdl-12750702

ABSTRACT

Clonal genetic aberrations in tumour cells provide critical information for the development of new diagnostic and therapeutic strategies for patients. In paediatric T-cell acute lymphoblastic leukaemia (T-ALL) chromosomal translocations are present in 30-35% of cases. HOX11 and the closely related HOX11L2 genes play a key role in T-ALL. HOX11 is aberrantly activated by either of the two chromosomal translocations, t(7;10) and t(10;14). In this study, HOX11 expression levels were measured by real-time quantitative reverse-transcriptase polymerase chain reaction. We show that leukaemic blasts from 15/76 (19.7%) paediatric T-ALL patients expressed the HOX11 gene at high level and 22/76 (28.9%) at low level, yet the reported frequency for chromosomal rearrangement of 10q24 is 4-7%. Direct cytogenetic analysis revealed that only 2/16 specimens that showed HOX11 expression exhibited abnor-malities at 10q24. These results confirm and extend our previously published findings, and implicate mechanisms other than gross chromosomal translocations for the deregulation of HOX11. Analysis of clinical outcome for the whole study group showed a trend for better outcome for patients with leukaemic blasts expressing HOX11 at high level. A statistically significant difference in clinical outcome was found in a subgroup of 20 patients treated for high-risk disease on CCG-1901 from the Children's Cancer Group, where HOX11 expression in leukaemic blasts conferred a prognostic advantage (P=0.01).


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 10/genetics , Homeodomain Proteins/genetics , Leukemia-Lymphoma, Adult T-Cell/genetics , Oncogene Proteins/genetics , Translocation, Genetic/genetics , Bone Marrow , Cell Lineage , Child , Child, Preschool , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 7/genetics , Cytogenetic Analysis , DNA Primers/chemistry , Female , Gene Expression , Homeodomain Proteins/metabolism , Humans , Infant , Male , Oncogene Proteins/metabolism , Ploidies , Polymerase Chain Reaction , Proto-Oncogene Proteins , RNA, Messenger/genetics , Survival Rate , Tumor Cells, Cultured
8.
J Clin Oncol ; 19(7): 1916-25, 2001 Apr 01.
Article in English | MEDLINE | ID: mdl-11283123

ABSTRACT

PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children's Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/economics , Health Care Costs , Length of Stay/economics , Outcome Assessment, Health Care/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/economics , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Child , Child, Preschool , Clinical Trials as Topic/statistics & numerical data , Cost-Benefit Analysis , Disease-Free Survival , Drug Administration Schedule , Humans , Outcome Assessment, Health Care/economics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recurrence
9.
Blood ; 97(2): 572-4, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11154239

ABSTRACT

The genes at the INK4A/ARF locus at 9p21 are frequently involved in human cancer. Virtually all p16(INK4A) exon 2 (henceforth called p16) inactivation in pediatric acute lymphoblastic leukemia (ALL) occurs by gene deletion. The results of this study illustrate that real-time quantitative polymerase chain reaction is capable of detecting gene deletion in primary patient specimens with a precision not previously achieved by conventional methods. Importantly, this assay includes the detection of hemizygous deletions. The study revealed, strikingly, that the risk ratio for relapse for hemizygous deletion compared with no deletion was 6.558 (P =.00687) and for homozygous deletion was 11.558 (P =.000539). These results confirm and extend the authors' previous findings that homozygous deletion of p16 in pediatric ALL patients is an independent prognostic indicator of outcome from therapy.


Subject(s)
Carrier Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Actuarial Analysis , Adolescent , Bone Marrow , Child , Child, Preschool , Cyclin-Dependent Kinase Inhibitor p16 , Disease-Free Survival , Female , Gene Deletion , Genes, Tumor Suppressor , Genotype , Humans , Infant , Infant, Newborn , Male , Polymerase Chain Reaction/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Predictive Value of Tests , Prognosis , Recurrence , Treatment Outcome
10.
J Clin Oncol ; 18(22): 3837-44, 2000 Nov 15.
Article in English | MEDLINE | ID: mdl-11078497

ABSTRACT

PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12-14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12-14 in children with newly diagnosed ALL treated on Children's Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12-14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12-14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12-14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12-14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P =.04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P =.25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P =.72). CONCLUSION: Aberrations of 13q12-14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 13 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Chromosome Breakage , Chromosome Deletion , Clinical Trials as Topic , Cohort Studies , Disease-Free Survival , Humans , Infant , Karyotyping , Ploidies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Treatment Outcome
11.
J Clin Oncol ; 18(18): 3262-72, 2000 Sep 15.
Article in English | MEDLINE | ID: mdl-10986059

ABSTRACT

PURPOSE: To determine the incidence, risk factors, and morbidity for osteonecrosis (ON) in children with acute lymphoblastic leukemia (ALL) treated with intensive chemotherapy including multiple, prolonged courses of corticosteroid. PATIENTS AND METHODS: The occurrence of symptomatic ON was investigated retrospectively in 1, 409 children ages 1 to 20 years old receiving therapy for high-risk ALL on Children's Cancer Group (CCG) protocol CCG-1882. RESULTS: ON was diagnosed in 111 patients (9.3% +/- 0.9%, 3-year life-table incidence). The incidence was higher for older children (> or = 10 years: 14.2% +/- 1.3% v < 10 years: 0.9% +/- 0.4%; P: <.0001), especially females 10 to 15 years old and males 16 to 20 years old (19.2% +/- 2.3% and 20.7% +/- 4.7%, respectively). In patients 10 to 20 years old, the incidence of ON was higher for females versus males (17.4% +/- 2.1% v 11.7% +/- 1.6%, respectively; P: =.03) and for patients randomized to receive two 21-day dexamethasone courses versus one course (23.2% +/- 4.8% v 16.4% +/- 4.3%, respectively; P: =.27). Among ethnic groups, whites had the highest incidence and blacks the lowest, with other groups intermediate (16.7% +/- 1.4% v 3.3% +/- 2.3% v 6.7% +/- 2.2%, respectively; P: =.003). There was no difference in event-free survival in patients with or without ON. ON was diagnosed within 3 years of starting ALL therapy in all but one patient, involved weight-bearing joint(s) in 94% of patients, and was multifocal in 74% of patients. Symptoms of pain and/or immobility were chronic in 84% of patients, with 24% having undergone an orthopedic procedure and an additional 15% considered candidates for surgery in the future. CONCLUSION: Children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/adverse effects , Glucocorticoids/adverse effects , Osteonecrosis/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prednisone/adverse effects , Adolescent , Adult , Age Factors , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Clinical Trials as Topic , Cohort Studies , Dexamethasone/administration & dosage , Female , Glucocorticoids/administration & dosage , Humans , Incidence , Infant , Joint Diseases/chemically induced , Male , Osteonecrosis/epidemiology , Osteonecrosis/therapy , Prednisone/administration & dosage , Prognosis , Risk Factors , Sex Factors
12.
Cancer ; 88(8): 1945-54, 2000 Apr 15.
Article in English | MEDLINE | ID: mdl-10760773

ABSTRACT

BACKGROUND: The authors have determined the prognostic significance of cytogenetically detectable 12p abnormalities, which are frequent in children with acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk-adjusted protocols of the Children's Cancer Group (CCG). METHODS: The presence of an abnormal 12p was identified among 1880 children with newly diagnosed ALL; outcome was assessed by standard life table methods. RESULTS: A total of 174 cases (9%) had cytogenetically detectable 12p abnormalities; the majority of cases had a balanced translocation, a del(12p), or an add(12p). In the overall cohort, event free survival (EFS) at 6 years was similar for patients with or without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P = 0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31-0.85). There was a trend for improved EFS for those with abnormalities in both chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10-1.55) and those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18-1.09). Among T-lineage ALL patients, there was a trend for worse outcome for abnormal versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78-4.93). There was no difference in EFS for the 12 patients with a dic(9;12) compared with patients lacking an abnormal 12p. CONCLUSIONS: These data suggest that although a cytogenetically detectable 12p aberration is a favorable risk factor for children with ALL and pseudodiploidy, it is not prognostic for the overall group of pediatric ALL patients treated with contemporary therapies of the CCG.


Subject(s)
Chromosome Aberrations , Chromosome Disorders , Chromosomes, Human, Pair 12/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Retrospective Studies , Risk Assessment
13.
Leuk Lymphoma ; 36(5-6): 467-78, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10784391

ABSTRACT

We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%) children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (>50 chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and q25. Patients with a del(6q) were more likely to have T-lineage ALL (p < 0.001), a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only half of these patients were classified as poor risk. Event-free survival at 6 years was similar for patients with or without a del(6q), with estimates of 77% (SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also observed within NCI poor and standard risk groups. Thus, cytogenetically detectable del(6q) is not associated with adverse risk in pediatric ALL.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 6 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis
14.
J Clin Oncol ; 18(9): 1876-87, 2000 May.
Article in English | MEDLINE | ID: mdl-10784628

ABSTRACT

PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children's Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P =.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.


Subject(s)
Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 5/genetics , Diploidy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Trisomy/genetics , Child , Child, Preschool , Female , Humans , Infant , Karyotyping , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Predictive Value of Tests , Prognosis , Treatment Outcome
15.
J Pediatr Hematol Oncol ; 22(1): 27-33, 2000.
Article in English | MEDLINE | ID: mdl-10695818

ABSTRACT

PURPOSE: Children with acute lymphoblastic leukemia (ALL) who had bulky disease (lymphomatous features) at diagnosis had the highest rate of testicular relapse (20%) of any ALL subgroup on previous Children's Cancer Group (CCG) studies in the late 1980s. To limit curative, but sterilizing, testicular irradiation to those with testicular disease, testicular biopsies were performed to detect occult testicular disease within the first 6 months of treatment. Testicular irradiation then was provided to those with occult disease to increase disease-free survival. Identification of those with occult disease was believed to be a factor that would influence ultimate survival in such patients in that era. PATIENTS AND METHODS: One hundred ninety-nine patients had bilateral testicular wedge biopsies performed during the first maintenance therapy phase of the four different chemotherapy regimens. Patients with positive biopsy results were treated with testicular irradiation and continued on therapy. RESULTS: Eleven of 199 biopsy results (5.5%) were judged positive. Patients with positive biopsy results given testicular radiation had a 45% subsequent adverse event rate, compared with 36% for those with a negative biopsy results (P = 0.4). The survival rates for the two groups were similar. The low rate of positive biopsy specimens resulted in discontinuation of the procedure before closure of the study. CONCLUSION: Positive testicular biopsy results early in remission identified patients at a slightly higher risk of subsequent adverse events but did not influence survival. However, because negative biopsy results (94.5%) did not alter the prescribed treatment, the small number of positive biopsy results did not warrant undertaking the procedure in most male patients with ALL, and this procedure was abandoned.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Testicular Neoplasms/pathology , Testis/pathology , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Child , Child, Preschool , Cranial Irradiation , Disease-Free Survival , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Testicular Neoplasms/diagnosis , Testicular Neoplasms/radiotherapy , Time Factors
16.
Leukemia ; 14(12): 2223-33, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11187913

ABSTRACT

Since 1968, the Children's Cancer Group (CCG) has treated more than 16,000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% +/- 10% for the 1983-1988 series and 72% +/- 1% for the 1988-1995 series (P< 0.0001). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Münster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Child , Child, Preschool , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/radiotherapy , Treatment Outcome
17.
Blood ; 94(12): 4036-45, 1999 Dec 15.
Article in English | MEDLINE | ID: mdl-10590047

ABSTRACT

We have determined the prognostic significance of hypodiploidy (<46 chromosomes) in a large cohort of children with acute lymphoblastic leukemia (ALL) treated by the Children's Cancer Group. Among 1,880 patients, 110 (5.8%) had hypodiploid karyotypes: 87 had 45 chromosomes, 15 had 33 to 44 chromosomes, none had 29 to 32 chromosomes, and 8 had 24 to 28 chromosomes (near-haploidy). Six-year event-free survival (EFS) estimates for patients with 45 chromosomes, 33 to 44 chromosomes, or 24 to 28 chromosomes were 65% (standard deviation [SD], 8%), 40% (SD, 18%), and 25% (SD, 22%), respectively (log rank, P =.002; test for trend, P =.0009). The combined hypodiploid group had worse outcome than nonhypodiploid patients, with 6-year EFS of 58% (SD, 7%) and 76% (SD, 2%), respectively (P <.0001). EFS for the subgroup with 45 chromosomes was similar to that of patients with pseudodiploidy (P =.43) or 47 to 50 chromosomes (P =.76). None of the patients with 24 to 28 chromosomes had a t(4;11), a t(9;22), or a t(1;19), and most received highly intensive therapy. The adverse risk associated with 33 to 44 and 24 to 28 chromosomes remained significant in multivariate analyses adjusted for important risk factors including age, white blood cell count, and Philadelphia chromosome status. Thus, hypodiploidy with less than 45 chromosomes, particularly 24 to 28 chromosomes, is a significant adverse risk factor despite treatment with contemporary intensive therapies.


Subject(s)
Ploidies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Female , Humans , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Predictive Value of Tests , Prognosis , Survival Analysis
18.
Blood ; 94(5): 1537-44, 1999 Sep 01.
Article in English | MEDLINE | ID: mdl-10477677

ABSTRACT

Cytogenetic abnormalities of chromosome arm 9p occur frequently in children with acute lymphoblastic leukemia (ALL). We analyzed 201 such cases (11%) in 1,839 children with newly diagnosed ALL treated between 1989 and 1995 on risk-adjusted protocols of the Children's Cancer Group (CCG). The majority of patients (131; 65%) with a 9p abnormality were classified as higher risk. Nearly all patients had complex karyotypes; most cases had deletions of 9p, add/der(9p), a dicentric involving chromosome arm 9p, and/or balanced translocations and inversions involving 9p. Event-free survival (EFS) estimates at 6 years for patients with and without a 9p aberration were 61% (standard deviation [SD] = 5%) and 76% (SD = 2%; P <.0001). In addition, patients with a 9p abnormality had an increased cumulative incidence of both marrow (P =.04) and central nervous system (P =.0001) relapses. Overall survival also was significantly worse for patients with an abnormal 9p (P <.0001). These effects were most pronounced in standard-risk patients (age 1 to 9 years with white blood cell count <50,000/microL): 6-year EFS of 61% (SD = 9%) versus 80% (SD = 2%; P <.0001). Also, a 9p aberration was an adverse risk factor for B-lineage, but not T-lineage patients. The effect of 9p status on EFS was attenuated, but maintained in a multivariate analysis of EFS after adjustment for Philadelphia chromosome status, age, white blood cell (WBC) count, sex, race, and ploidy group (P =.01). Thus, abnormalities of chromosome arm 9p identify a subgroup of standard-risk patients with increased risk of treatment failure.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 9 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Female , Humans , Infant , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Risk Factors
19.
J Pediatr Hematol Oncol ; 21(4): 260-7, 1999.
Article in English | MEDLINE | ID: mdl-10445887

ABSTRACT

PURPOSE: To describe patterns of central venous catheter (CVC) use and determine the risk of infection associated with a catheter in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Children with ALL (n = 1934), participating in Children's Cancer Group studies for good-prognosis ALL (CCG-1881) and intermediate-risk ALL (CCG-1891) were evaluated in a retrospective case-control study. The presence of a catheter and the occurrence of infectious complications were recorded after each treatment phase. RESULTS: Young age and enrollment in the intermediate-risk study were associated with higher rates of catheter use. During each of the first four phases of therapy, the adjusted risk of infection was two- to fourfold higher when a catheter was in place. The proportion of patients with infection during the first four phases of therapy was 2.6 times higher with a CVC (14.4% versus 5.7%). Catheter use was associated with significantly increased hospitalization rates during induction, consolidation, and interim maintenance, but not during delayed intensification. A catheter did not significantly increase the risk of fever during neutropenia. CONCLUSION: The presence of a CVC increases the risk of infection during the early phases of low-intensity therapy for ALL.


Subject(s)
Antineoplastic Agents/administration & dosage , Catheterization, Central Venous/adverse effects , Infections/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Case-Control Studies , Child , Child, Preschool , Female , Humans , Incidence , Male , Retrospective Studies , Risk , United States
20.
Leukemia ; 13(5): 679-86, 1999 May.
Article in English | MEDLINE | ID: mdl-10374870

ABSTRACT

Infants less than 1 year of age at diagnosis of acute lymphoblastic leukemia (ALL) have a poor prognosis, which has been attributed primarily to a breakpoint in chromosomal band 11q23 or the MLL gene. Most infants with an 11q23 breakpoint have a t(4;11)(q21 ;q23). We studied the cytogenetics of the leukemia cells of 56 infants on CCG-1883, a single-arm clinical treatment protocol for infant ALL. Twenty-one patients had t(4;11)(q21;q23), seven had other rearrangements with breakpoints in 11q23 (other 11q23), 16 had normal chromosomes, two had t(1;19)(q32;p13), one had >50 chromosomes, and nine had non-recurring structural abnormalities. To determine whether there is a difference in outcome for infants with t(4;11), other 11q23 and the remaining patients, we compared event-free survival (EFS) and other clinical and laboratory features of the above infants. Infants without t(4;11) and those with other 11q23 rearrangements had significantly better EFS than those with t(4;11) (P= 0.007 and P= 0.02, respectively). t(4;11) correlated with age less than 6 months and with CD10 negativity, both of which also were poor prognostic indicators. After adjustment for age, there was still a significant difference in EFS between patients with t(4;11) and those with other 1lq23 rearrangements (P=0.02), and between patients with t(4;11) and those without t(4;11) (P=0.04). Among CD10 negative patients, t(4;11) was associated with a worse EFS (P=0.01). Multivariate analysis showed that after adjusting for a variety of clinical and laboratory features, t(4;11) was the most important prognostic factor for poor outcome, and patients with other 11q23 rearrangements had as good an outcome as the remaining patients without t(4;11).


Subject(s)
Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 4 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Translocation, Genetic , Disease-Free Survival , Female , Humans , Infant , Infant, Newborn , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis
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