RESUMO
Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1-/- mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.
Assuntos
Células-Tronco Hematopoéticas/patologia , Neurofibromatose 1/metabolismo , Proteínas/fisiologia , Proteínas ras/fisiologia , Animais , Divisão Celular , Células Cultivadas , Criança , Proteínas Ativadoras de GTPase , Genes da Neurofibromatose 1 , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Guanosina Trifosfato/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Neurofibromatose 1/patologia , Neurofibromina 1 , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Proteínas Ativadoras de ras GTPase , Proteínas ras/metabolismoRESUMO
In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.
Assuntos
Transplante de Medula Óssea/métodos , Leucemia Mieloide Aguda/terapia , Indução de Remissão/métodos , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Estudos Prospectivos , Condicionamento Pré-Transplante/métodos , Transplante AutólogoRESUMO
BACKGROUND: Most patients receiving therapy for acute myeloid leukemia (AML) enter an interval in which leukemic blast cells cannot be detected by light microscopy (i.e., morphologic remission). However, many of these patients experience a subsequent relapse. Multidimensional flow cytometry, which allows the discrimination of antigens expressed on normal and malignant cells, can detect small numbers of cancer cells in bone marrow or peripheral blood specimens. This technique enables the detection of one leukemic blast cell among 10(3) to 10(2) normal regenerating hematopoietic cells. PURPOSE: We determined whether the presence of residual leukemic blast cells, identified in the bone marrow of pediatric patients with AML by use of multidimensional flow cytometry, would be predictive of subsequent leukemic relapse. METHODS: Multidimensional flow cytometry was performed on 205 marrow specimens collected throughout the course of treatment from 39 patients who had achieved morphologic remission. The analyses employed monoclonal antibodies directed against CD45 in combination with mixed pairs of monoclonal antibodies directed against 10 other antigens. A time-varying Cox regression analysis that controlled for sample time intervals, age, sex, morphologic classification of disease, and white blood cell count at diagnosis was used to relate the multidimensional flow cytometric results to the risk of relapse after achieving remission. Reported P values are two-sided. RESULTS: Thirty-five of the 39 patients had bone marrow specimens available from the time that first morphologic remission was achieved. Leukemic blast cells were detected in the specimens from 19 (54%) of these 35 patients. Twenty-five of the 35 patients did not receive an allogeneic (i.e., from a different genetic background) bone marrow transplant during first morphologic remission, and 13 of 14 with residual leukemic cells experienced a relapse at a median time of 153 days after diagnosis (range, 48-863 days). Nine of the 11 patients who did not receive an allogeneic bone marrow transplant and lacked evidence of leukemic blast cells at first morphologic remission relapsed at a median time of 413 days after diagnosis (range, 321-794 days). Among the 10 individuals who received an allogeneic bone marrow transplant during first morphologic remission, five were positive for leukemic blast cells and five were negative; one of these patients (positive for leukemic blast cells) experienced a relapse 265 days after diagnosis, and three others died of transplant-related complications. The estimated risk of relapse during intervals of multidimensional flow cytometric positivity (i.e., intervals of remission for which the immediately preceding cytometry measurement was positive) was 2.8 times greater than that during negative intervals (95% confidence interval = 1.1-7.0; P = .02). CONCLUSIONS AND IMPLICATIONS: Multidimensional flow cytometry identifies residual leukemia in more than half of the patients with AML who are in morphologic remission. The detection of leukemic blast cells in these patients by multidimensional flow cytometry is predictive of a more rapid relapse.
Assuntos
Citometria de Fluxo , Leucemia Mieloide/diagnóstico , Doença Aguda , Adolescente , Anticorpos Monoclonais , Antígenos de Neoplasias/imunologia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem , Lactente , Leucemia Mieloide/imunologia , Masculino , Neoplasia Residual , Valor Preditivo dos Testes , Prognóstico , Recidiva , RiscoRESUMO
Translocations at chromosomal band 11q23 characterize most de novo acute lymphoblastic leukemias (ALL) of infants, acute myeloid leukemias (AML) of infants and young children, and secondary AMLs following epipodophyllotoxin exposure. The chromosomal breakpoints at 11q23 have been cloned from isolated cases of de novo ALL and AML. Using an 859-base pair BamHI fragment of human ALL-1 complementary DNA that recognizes the genomic breakpoint region for de novo ALL and AML, we investigated two cases of secondary AML that followed etoposide-treated primary B-lineage ALL. In the first case, the translocation occurred between chromosomes 9 and 11 and the breakpoint at 11q23 localized to the same 9-kilobase region of the ALL-1 gene that is disrupted in most of the de novo leukemias. In the second case the translocation was between chromosomes 11 and 19. The breakpoint occurred outside of the ALL-1 breakpoint cluster region.
Assuntos
Leucemia Monocítica Aguda/genética , Podofilotoxina/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Escolar , Cromossomos Humanos Par 11/efeitos dos fármacos , Cromossomos Humanos Par 11/fisiologia , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , DNA-Citosina Metilases/metabolismo , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Humanos , Leucemia Monocítica Aguda/induzido quimicamente , Masculino , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Podofilotoxina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Translocação Genética/efeitos dos fármacosRESUMO
Human leukemias with 11q23 translocations occur sporadically and after cancer treatment with DNA topoisomerase II-targeted drugs. To investigate this process, we examined DNA topoisomerase II cleavage in vitro in subclones of the normal 11q23 genomic homologue and a t(9;11) translocation breakpoint junction. Cleavage was assayed with limiting dilutions of enzyme in the presence or absence of epipodophyllotoxin and ATP. The strongest sites of cleavage coincided with the t(9;11) breakpoint site and two other translocation breakpoint sites within the normal homologue. These results support the involvement of DNA topoisomerase II in the translocation process at chromosome band 11q23.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 9 , DNA Topoisomerases Tipo II/fisiologia , Proto-Oncogenes , Fatores de Transcrição , Translocação Genética , Sequência de Bases , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase , Humanos , Íntrons , Dados de Sequência Molecular , Proteína de Leucina Linfoide-MieloideRESUMO
We have examined a t(9;11)(p22;q23) chromosome translocation in an acute myeloid leukemia of an infant. The breakpoints on the two chromosomes occurred within introns of the involved genes: AF-9 on chromosome 9, and ALL-1 on chromosome 11. Sequence analysis identified heptamers flanking the breakpoints on both chromosomes 9 and 11, suggesting that the V-D-J recombinase was involved in the translocation. The presence of an N-region between the two chromosomes supports the hypothesis that a mistake in V-D-J joining was involved in the genesis of the translocation and indicates that terminal deoxynucleotidyl transferase was expressed in the cells from which this acute myeloid leukemia originated. In addition, potential topoisomerase II DNA-binding sites were found near the breakpoints of both chromosomes, suggesting the involvement of altered topoisomerase II activity in this translocation. Altered topoisomerase II activity in the presence of an active V-D-J recombinase may be a pathogenetic mechanism of acute myeloid leukemia with rearrangements at 11q23.
Assuntos
Cromossomos Humanos Par 9 , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/metabolismo , Leucemia Mieloide Aguda/genética , Translocação Genética , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação , Southern Blotting , Cromossomos Humanos Par 11 , DNA Nucleotidiltransferases/metabolismo , Humanos , Íntrons , Leucemia Mieloide Aguda/metabolismo , Dados de Sequência Molecular , Mapeamento por Restrição , Homologia de Sequência do Ácido Nucleico , VDJ RecombinasesRESUMO
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a new nucleoside antimetabolite, was evaluated in a phase I trial involving children with refractory cancers. The drug was administered i.v. as a 10-min infusion daily for 5 consecutive days repeated at 3-week intervals. The dose ranged from 550 to 3300 mg/sq m/day. Seventeen patients received 23 courses and were evaluable for toxicity. The maximally tolerated dose was 2200 mg/sq m/day. The major dose-limiting toxicities were nonhematological. Neurotoxicity, including headache, drowsiness, and irritability, was common and was the principal dose-limiting toxicity at the higher doses. Severe myalgias were also dose limiting in one patient. Other side effects were mild, reversible elevations in serum transaminases; nausea, vomiting, and diarrhea; mild hypertension; dysphagia; and exfoliative dermatitis of the hands and feet. Myelotoxicity was not significant. The pharmacokinetics of tiazofurin was studied in 16 patients. Plasma disappearance was triphasic with half-lives of 9.7 min, 1.6 h, and 5.5 h. Clearance was dose related, ranging from 120 ml/min/sq m at 550 mg/sq m/day to 70 ml/min/sq m at 3300 mg/sq m/day. The primary route of elimination was renal with 85% of the drug recoverable in the urine as the parent compound in the 24 h following administration.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ribavirina/uso terapêutico , Ribonucleosídeos/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Avaliação de Medicamentos , Humanos , Rim/efeitos dos fármacos , Cinética , Ribavirina/efeitos adversos , Ribavirina/análogos & derivados , Ribavirina/metabolismoRESUMO
We used single-strand conformation polymorphism (SSCP) analysis of p53 exons 4-8 to screen for possible mutations in 25 pediatric de novo leukemias with translocations of the MLL gene at chromosome band 11q23. Of the 25 patients, 21 were infants. Fifteen cases were acute myeloid leukemia (AML), eight were acute lymphoblastic leukemia (ALL), and two cases were biphenotypic. Nineteen cases were studied at diagnosis and six at time of relapse. p53 mutations were absent in all 19 cases studied at the time of diagnosis. The only mutation was a TGC-->TTC transversion (cys-->phe) at codon 141 in exon 5 in a case of infant ALL at relapse that occurred by subclone evolution after MLL gene translocation. We previously showed that p53 mutations are also absent in pediatric treatment-related leukemias with MLL gene translocations. The absence of p53 mutations at initial transformation may suggest that the anti-apoptotic effect of mutant p53 is not important in leukemias with MLL gene translocations. Alternatively, exogenous DNA damage may be the common feature in treatment-related and de novo cases. Since MLL gene translocations may occur through DNA repair and wild-type p53 is central to DNA repair, the absence of p53 mutations raises the possibility that wild-type p53, not mutant p53, may be important in the genesis of leukemias with these translocations.
Assuntos
Cromossomos Humanos Par 11 , Proteínas de Ligação a DNA/genética , Genes p53 , Leucemia Mieloide Aguda/genética , Modelos Genéticos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proto-Oncogenes , Fatores de Transcrição , Translocação Genética , Criança , Pré-Escolar , Bandeamento Cromossômico , Mapeamento Cromossômico , Éxons , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Recém-Nascido , Cariotipagem , Masculino , Proteína de Leucina Linfoide-Mieloide , Polimorfismo Conformacional de Fita Simples , Recidiva , Dedos de ZincoRESUMO
PURPOSE: Although remission can be achieved in 80% of children with acute myelogenous leukemia (AML), many patients experience relapse. Because interleukin-2 (IL-2) can induce remission in patients with overt evidence of AML, we hypothesized that IL-2 given to patients in first remission after intensive consolidation chemotherapy might prevent relapse. This study sought to determine whether such an approach was feasible. PATIENTS AND METHODS: Twenty-one patients in complete remission received IL-2 after completion of treatment on Children's Cancer Group (CCG) protocol 2941. Recombinant IL-2 9 x 10(6) IU/m2 daily by continuous intravenous infusion (c.i.v.) was given for 4 days. After 4 days rest, IL-2 1.6 x 10(6) IU/m2 daily c.i.v. was resumed for 10 days. We monitored patients for toxicity and measured absolute lymphocyte count, the absolute count of cells that express CD56 and CD3 antigen, and soluble IL-2 receptor alpha-chain (sIL-2R alpha) levels before the start of IL-2 and after completion of each of the two courses of IL-2. RESULTS: Observed toxicities included fever (57%), vascular leak (48%), hypotension (38%), tachycardia (14%), rash (29%), septicemia (5%), thrombocytopenia (29%), elevated transaminase (14%), electrolyte disturbance (29%), and hyperglycemia (10%). No patient required cardiac pressors or transfer to an intensive care unit. All patients studied developed an increase in lymphocyte count, CD56 count, CD3 count, and sIL-2R alpha levels after treatment with IL-2. CONCLUSION: This schedule of IL-2 was reasonably well tolerated by children with AML in first remission. After treatment, increased levels of sIL-2R alpha were observed. CCG is conducting a randomized prospective trial to assess the efficacy of IL-2 to prevent the relapse of AML (CCG-2961).
Assuntos
Interleucina-2/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Complexo CD3/análise , Antígeno CD56/análise , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Citometria de Fluxo , Humanos , Lactente , Interleucina-2/efeitos adversos , Leucemia Mieloide Aguda/imunologia , Masculino , Receptores de Interleucina-2/sangue , Proteínas Recombinantes/uso terapêutico , Indução de RemissãoRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Custos de Cuidados de Saúde , Tempo de Internação/economia , Avaliação de Resultados em Cuidados de Saúde/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/economia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise Custo-Benefício , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Avaliação de Resultados em Cuidados de Saúde/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , RecidivaRESUMO
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.
Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 5/genética , Diploide , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Trissomia/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Cariotipagem , Masculino , Análise Multivariada , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Valor Preditivo dos Testes , Prognóstico , Resultado do TratamentoRESUMO
PURPOSE: The nonrandom translocation t(1;19) has been associated with poor outcome in pediatric B-lineage acute lymphoblastic leukemia (ALL). Because most patients treated by contemporary therapies now achieve improved outcomes, we have reassessed the prognostic significance of t(1;19). PATIENTS AND METHODS: Cytogenetic data were accepted for 1,322 children (<21 years old) with newly diagnosed ALL enrolled between 1988 and 1994 on risk-adjusted studies of the Children's Cancer Group (CCG). Forty-seven patients (3.6%) were t(1;19) positive (+); 1,275 (96.4%) were t(1;19) negative (-). Clinical characteristics and treatment outcome were compared using standard methods. RESULTS: Translocation (1;19)+ patients were more likely than t(1;19)- patients to be 10 years of age or greater (P < .001) or CD10+ CD19+ CD34- (P < .0001), or nonwhite (P = .02). Patients with a balanced t(1;19) were less likely to be hyperdiploid than patients with an unbalanced der(19)t(1;19). Event-free survival (EFS) was similar for the overall group of t(1;19)+ and t(1;19)- patients, with 4-year estimates of 69.5% (SD, 6.8%) and 74.8% (SD, 1.3%; P = .48), respectively. However, patients with unbalanced der(19)t(1;19) had significantly better outcomes than patients with balanced t(1;19): 4-year EFS were 80.6% (SD, 7.1%) and 41.7% (SD, 13.5%), respectively (P = .003). These differences were maintained within the individual studies analyses and after exclusion of t(1;19)+ patients whose cells were hyperdiploid with more than 50 chromosomes. CONCLUSION: The overall group of t(1;19)+ patients, as well as the subgroup with an unbalanced der(19)+ (1;19) had outcomes similar to that of t(1;19)- patients, whereas patients with balanced t(1;19) had poorer outcomes. Thus, although the overall prognostic significance of t(1;19) has been obviated by contemporary risk-adjusted protocols, the balanced t(1;19) translocation remains an adverse prognostic factor.
Assuntos
Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Imunofenotipagem , Lactente , Cariotipagem , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , PrognósticoRESUMO
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.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 13 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Pré-Escolar , Quebra Cromossômica , Deleção Cromossômica , Ensaios Clínicos como Assunto , Estudos de Coortes , Intervalo Livre de Doença , Humanos , Lactente , Cariotipagem , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado do TratamentoRESUMO
PURPOSE: Nonrandom chromosomal translocations are frequently observed in pediatric patients with acute lymphoblastic leukemia (ALL). Specific translocations, such as t(4;11) and t(9;22), identify subgroups of B-lineage ALL patients who have an increased risk of treatment failure. The current study was conducted to determine the prognostic significance of chromosomal translocations in T-lineage ALL patients. MATERIALS AND METHODS: The study included 169 children with newly diagnosed T-lineage ALL enrolled between 1988 and 1995 on risk-adjusted protocols of the Children's Cancer Group (CCG) who had centrally reviewed cytogenetics data. Outcome analyses used standard life-table methods. RESULTS: Presenting features for the current cohort were similar to those of concurrently enrolled patients for whom cytogenetic data were not accepted on central review. The majority of patients (80.5%) were assigned to CCG protocols for high-risk ALL and 86.4% had pseudodiploid (n = 80) or normal diploid (n = 66) karyotypes; modal chromosome number was not a significant prognostic factor. Overall, 103 of 169 (61%) patients had an abnormal karyotype, including 31 with del(6q), 29 with 14q11 breakpoints, 15 with del(9p), 11 with trisomy 8, nine with 11q23 breakpoints, nine with 14q32 translocations, and eight with 7q32-q36 breakpoints. Thirteen patients had the specific 14q11 translocation t(11;14)(p13;q11) and all were classified as poor risk. Patients with any of these translocations had outcomes similar to those with normal diploid karyotypes. CONCLUSION: Chromosomal abnormalities, including specific nonrandom translocations, were frequently observed in a large group of children with T-lineage ALL, but were not significant prognostic factors for this cohort. Thus, contemporary intensive treatment programs result in favorable outcomes for the majority of T-lineage ALL patients, regardless of karyotypic abnormalities, and such features do not identify patients at higher risk for relapse.
Assuntos
Aberrações Cromossômicas/genética , Leucemia-Linfoma de Células T do Adulto/genética , Adolescente , Criança , Pré-Escolar , Transtornos Cromossômicos , Estudos de Coortes , Citogenética , Intervalo Livre de Doença , Feminino , Humanos , Imunofenotipagem , Lactente , Cariotipagem , Leucemia-Linfoma de Células T do Adulto/classificação , Tábuas de Vida , Masculino , Prognóstico , Translocação GenéticaRESUMO
PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols. PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies. RESULTS: Most patients (>95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG- 1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG- 1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/microL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11). CONCLUSION: Outcome for infants on CCG-107 and CCG- 1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea , Terapia Combinada , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Fatores de Risco , Resultado do TratamentoRESUMO
In her 8 1/2 years of life, a girl with neurofibromatosis type 1 (NF1) developed four sequential primary malignant neoplasms: Wilms tumor, T-cell acute lymphoblastic leukemia, medulloblastoma and acute myeloid leukemia. The last three tumors were characterized by chromosomal abnormalities non-randomly associated with that particular disease. There was no evidence of germline p53 mutation or of mutation of p53 in the last two tumors. We hypothesize that an unusual mutation of the NF1 gene in this child promoted growth in tissues where the normal or mutated NF-1 gene product is usually silent or growth inhibitory.
Assuntos
Leucemia Mieloide Aguda/etiologia , Leucemia-Linfoma de Células T do Adulto/etiologia , Meduloblastoma/etiologia , Neoplasias Primárias Múltiplas/etiologia , Neurofibromatose 1/complicações , Tumor de Wilms/etiologia , Medula Óssea/patologia , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Criança , Feminino , Genes p53 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma de Células T do Adulto/genética , Meduloblastoma/genética , Neoplasias Primárias Múltiplas/genética , Neurofibromatose 1/genética , Tumor de Wilms/genéticaRESUMO
Based upon in vitro evidence of p53 involvement in lymphoid differentiation, we assessed immunoglobulin (Ig) and T-cell receptor (TCR) genes in five acute lymphoblastic leukemias (ALLs) with, and 24 ALLs without p53 mutations to compare their genotypic stages. Using Southern blot analysis and complementarity determining region III polymerase chain reaction (CDRIII PCR), 18 cases of B-lineage ALL and 11 cases of T-ALL were studied. Of 20 specimens from 18 B-lineage ALLs, two of four with p53 mutation and two of 16 without mutation had an unrearranged Ig and TCR genotype (p = 0.16; Fisher's exact test). Of 11 cases of T-ALL, the one case with p53 mutation had a rearranged TCR and Ig genotype and a case without mutation was unrearranged. The study indicates that p53 mutation is an infrequent feature of ALL found, nonetheless, in every genotypic subset. The p53 mutations in cases that do not further rearrange may support p53 involvement in lymphoid differentiation, but the heterogeneity in differentiation stages in cases both with and without p53 mutations suggests that regulation of early lymphoid maturation is multifactorial.
Assuntos
Genes p53 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Linfoma de Burkitt/genética , Diferenciação Celular/fisiologia , Criança , Pré-Escolar , Códon , Genótipo , Humanos , Imunofenotipagem , Lactente , Leucemia-Linfoma de Células T do Adulto/genética , Mutação , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
A variety of chromosomal translocations occur in pediatric T-cell acute lymphoblastic leukemia (T-ALL) in which a cellular oncogene or growth-related gene is translocated to the alpha/delta locus of the T-cell receptor gene. The t(8;14)(q24;q11) has been described at the cytogenetic and molecular level, but the disease associated with this translocation has not been defined clinically. Fifteen pediatric cases of leukemia/lymphoma with a t(8;14)(q24;q11) chromosomal translocation were collected from previous publications and institutional records. The estimated prevalence of this abnormality among all cases of ALL was 1%. The t(8;14)(q24;q11) disease was characterized by male predominance (10/15), a median age of 5.5 years (range 1.8-17 years), high white blood cell count (median 95 x 10(9)/l), central nervous system infiltration (4/11), bulky extramedullary leukemia (10/11), and T-cell immunophenotype (12/15). The median event-free survival was 4 months, and the median survival, 11 months. Seven cell lines with t(8;14)(q24;q11) were established from six of the cases; four were T-lymphoblastic, one was T-lymphoblastic, but expressed myeloid-related antigens, and two were predominantly myeloid. t(8;14)(q24;q11) leukemia/lymphoma and other ALLs involving 13(q11) have in common a high tumor burden, early spread to extramedullary sites, a propensity to form T-lymphoblastic or T-myeloid cell lines and, usually, an aggressive clinical course.
Assuntos
Aberrações Cromossômicas/genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Leucemia-Linfoma de Células T do Adulto/genética , Linfoma de Células T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Translocação Genética , Adolescente , Antígenos de Diferenciação/análise , Criança , Pré-Escolar , Transtornos Cromossômicos , Feminino , Humanos , Lactente , Cariotipagem , Linfoma de Células T/imunologia , MasculinoRESUMO
Acute myeloid leukemia (AML) is a heterogeneous group of diseases that differ in pattern of both remission and lineage involvement. The observation that hematopoiesis remains clonal in some patients with AML in complete clinical remission suggests that the acute phase may develop from a clinically unrecognized preleukemic clone. To investigate the characteristics and significance of clonal remissions in childhood AML, we used X-chromosome-linked polymorphisms to study granulocytes obtained from pediatric female patients in complete clinical remission. Remission granulocytes from only one of 17 evaluable patients were clonally derived, suggesting that clonal remission is an infrequent event in childhood AML.
Assuntos
Leucemia Mieloide/patologia , Doença Aguda , Adolescente , Criança , Pré-Escolar , Células Clonais , Feminino , Hematopoese , Humanos , Hipoxantina Fosforribosiltransferase/genética , Lactente , Fosfoglicerato Quinase/genética , Polimorfismo de Fragmento de RestriçãoRESUMO
The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.