Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Transplante de Medula Óssea , Criança , Humanos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Fatores de RiscoRESUMO
We previously reported preliminary findings that post induction imatinib mesylate (340 mg/m(2)/day), in combination with intensive chemotherapy, resulted in outcomes similar to blood and marrow transplant (BMT) for pediatric patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We now report 5-year outcomes of imatinib plus intensive chemotherapy in 91 children (1-21 years) with and without allogeneic BMT (N=91). We explore the impacts of additional chromosomal abnormalities and minimal residual disease (MRD) by flow cytometry on outcomes. The 5-year disease-free survival was similar for Cohort 5 patients, treated with chemotherapy plus imatinib (70%±12%, n=28), sibling donor BMT patients (65%±11%, n=21) and unrelated donor BMT patients (59±15%; P=0.60, n=13). Patients with additional cytogenetic abnormalities had worse outcomes (P=0.05). End induction (pre-imatinib) MRD was not prognostic for Cohort 5 or allogeneic BMT patients, although limited by small numbers. The re-induction rate following relapse was similar to other higher-risk ALL groups. Longer-term follow-up confirms our initial observation of substantially good outcomes for children and adolescents with Ph+ ALL treated with imatinib plus intensive chemotherapy with no advantage for allogeneic BMT.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Criança , Pré-Escolar , Aberrações Cromossômicas , Seguimentos , Humanos , Mesilato de Imatinib , Lactente , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Recidiva , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Neuroblastoma/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Coleta de Dados , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
From 1984 to 2001, the Pediatric Oncology Group (POG) conducted 12 acute lymphoblastic leukemia (ALL) studies. Ten-year event-free survival (EFS) for patients >12 months of age with B-precursor ALL on acute leukemia in children 14, 15 and 16 series were 66.7+/-1.2%, 68.1+/-1.4% and 73.2+/-2.1%, respectively. Intermediate dose methotrexate (ID MTX; 1 g/m(2)) improved outcomes for standard risk patients (10-year EFS 77.5+/-2.7% vs 66.3+/-3.1% for oral MTX). Neither MTX intensification (2.5 g/m(2)) nor addition of cytosine arabinoside/daunomycin/teniposide improved outcomes for higher risk patients. Intermediate dose mercaptopurine (1 g/m(2)) failed to improve outcomes for either group. Ten-year EFS for patients with T-cell ALL, POG 8704 and 9404 were 49.1+/-3.1% and 72.2+/-4.7%, respectively. Intensive asparaginase (10-year EFS 61.8 vs 42.7%) and high-dose MTX (5 g/m(2)) (10-year EFS 78.0 vs 65.8%) improved outcomes. There was a non-significant improvement in EFS for infants (10-year EFS 17.7+/-7.2-31.9+/-8.3%). Prognostic indicators for B-precursor ALL were age and WBC at diagnosis, gender, central nervous system disease, DNA index and cytogenetic abnormalities. Only gender was prognostic in T-cell ALL. In infants, WBC and MLL translocation were linked to inferior outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irradiação Craniana , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/terapia , Segunda Neoplasia Primária/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Terapia Combinada , Feminino , Seguimentos , Humanos , Imunofenotipagem , Lactente , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989-2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30-69) and 34% (95% CI 22-47) respectively. The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3-30). PFS rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.
Assuntos
Agonistas Mieloablativos/uso terapêutico , Sarcoma de Ewing/terapia , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Criança , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/secundário , Análise de Sobrevida , Transplante AutólogoRESUMO
In children with acute lymphoblastic leukemia (ALL) with isolated central nervous system (CNS) relapse and a human leucocyte antigen (HLA)-matched sibling, the optimal treatment after attaining second remission is unknown. We compared outcomes in 149 patients enrolled on chemotherapy trials and 60 HLA-matched sibling transplants, treated in 1990-2000. All patients achieved a second complete remission. Groups were similar, except the chemotherapy recipients were younger at diagnosis, less likely to have T-cell ALL and had longer duration (> or = 18 months) first remission. To adjust for time-to-transplant bias, left-truncated Cox's regression models were constructed. Relapse rates were similar after chemotherapy and transplantation. In both treatment groups, relapse rates were higher in older children (11-17 years; RR 2.81, P=0.002) and shorter first remission (< 18 months; RR 3.89, P<0.001). Treatment-related mortality rates were higher after transplantation (RR 4.28, P=0.001). The 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar after chemotherapy with irradiation and transplantation (66 and 58%, respectively). In the absence of an advantage for one treatment option over another, the data support use of either intensive chemotherapy with irradiation or HLA-matched sibling transplantation with total body irradiation containing conditioning regimen for children with ALL in second remission after an isolated CNS relapse.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Medula Óssea/métodos , Neoplasias do Sistema Nervoso Central/terapia , Histocompatibilidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Neoplasias do Sistema Nervoso Central/etiologia , Criança , Pré-Escolar , Coleta de Dados , Intervalo Livre de Doença , Feminino , Antígenos HLA , Humanos , Infiltração Leucêmica/etiologia , Infiltração Leucêmica/terapia , Estudos Longitudinais , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Radioterapia/métodos , Recidiva , Indução de Remissão , Irmãos , Condicionamento Pré-Transplante/métodos , Resultado do TratamentoRESUMO
For patients with acquired severe aplastic anemia without a matched sibling donor and not responding to immunosuppressive treatment, bone marrow transplantation from a suitable alternative donor is often attempted. We examined risks of graft failure, graft-versus-host disease and overall survival after 318 alternative donor transplants between 1988 and 1998. Sixty-six patients received allografts from 1-antigen and 20 from >1-antigen mismatched related donors; 181 from matched and 51 from mismatched unrelated donors. Most patients were young, had had multiple red blood cell transfusions and poor performance score at transplantation. We did not observe differences in risks of graft failure and overall mortality by donor type. The probabilities of graft failure at 100 days after 1-antigen mismatched related donor, >1-antigen mismatched related donor, matched unrelated donor and mismatched unrelated donor transplants were 21, 25, 15 and 18%, respectively. Corresponding probabilities of overall survival at 5 years were 49, 30, 39 and 36%, respectively. Although alternative donor transplantation results in long-term survival, mortality rates are high. Poor performance score and older age adversely affect outcomes after transplantation. Therefore, early referral for transplantation should be encouraged for patients who fail immunosuppressive therapy and have a suitable alternative donor.
Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Antígenos HLA/análise , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do TratamentoRESUMO
Children with Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) have only a 20% event-free survival when treated with chemotherapy alone. Bone marrow transplant (BMT) for patients with matched siblings has been associated with significantly better long-term survival. We asked whether children who lack a matched sibling donor would do as well if an alternative donor was utilized. Between 1987 and 2002, we transplanted 29 children and adolescents using either an unrelated donor (23) or a mismatched family member (six). The conditioning regimen included cytosine-arabinoside, cyclophosphamide and total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of T-cell depletion (antibody T10B9 or OKT3 and complement) with post transplant cyclosporine (CSA). All patients engrafted. Four developed grades III-IV acute GVHD. Three of 24 evaluable patients developed extensive chronic GVHD. Two patients died of relapse (7%). Two long-term survivors (>6 years) died of malignant glioblastoma multiforme. Event-free survival at 3, 5, and 10 years is 56, 51, and 46%, respectively. Five of six patients in >CR2 or relapse at the time of transplant died. Our data should encourage the use of alternative donor transplants early in the course of disease for children with Ph+ ALL.
Assuntos
Transplante de Medula Óssea , Seleção do Doador , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Seleção do Doador/métodos , Feminino , Glioblastoma/mortalidade , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Depleção Linfocítica/métodos , Depleção Linfocítica/mortalidade , Masculino , Segunda Neoplasia Primária/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/efeitos adversos , Irradiação Corporal Total/métodos , Irradiação Corporal Total/mortalidadeRESUMO
From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos Antineoplásicos/normas , Leucemia Mieloide/terapia , Doença Aguda , Adolescente , Transplante de Medula Óssea , Criança , Pré-Escolar , Citarabina/uso terapêutico , Relação Dose-Resposta a Droga , Síndrome de Down/complicações , Síndrome de Down/tratamento farmacológico , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/complicações , Leucemia Mieloide/mortalidade , Prognóstico , Indução de Remissão/métodos , Análise de Sobrevida , Resultado do TratamentoRESUMO
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.
Assuntos
Linfoma de Burkitt/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 4/genética , Trissomia/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/mortalidade , Criança , Pré-Escolar , Aberrações Cromossômicas , Intervalo Livre de Doença , Humanos , Lactente , National Institutes of Health (U.S.) , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Sociedades Médicas , Trissomia/diagnóstico , Estados UnidosRESUMO
We reported that children with B-progenitor-cell acute lymphoblastic leukemia (BpALL) treated in the early 1980s whose lymphoblasts accumulated high levels of methotrexate (MTX) and of methotrexate polyglutamates (MTXPGs) in vitro had an improved 5-year event-free survival (EFS) (65% (standard error (s.e.) 12%) vs 22% (s.e. 9%)). We repeated this study in children with BpALL treated in the early 1990s. The major change in treatment was the addition of 12 24-h infusions of 1 g/M2 MTX with leucovorin rescue (IDMTX). In 87 children treated on Pediatric Oncology Group (POG) study 9005 and POG 9006, the 5-year EFS for those whose lymphoblasts accumulated high levels of MTX and MTXPGs (79.2%, s.e. 8.3%) was not significantly different from that of patients with lesser accumulation of MTX and MTXPGs (77.7%, s.e. 5.4%). These findings support the notion that higher dose MTX therapy has contributed to increased cure, particularly for patients whose lymphoblasts accumulate the drug less well.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Metotrexato/análogos & derivados , Metotrexato/farmacocinética , Ácido Poliglutâmico/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Linfócitos B/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/farmacocinética , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The recombinant urate oxidase, rasburicase (Elitek, Sanofi-Synthelabo, Inc.), has recently received regulatory approval for the prevention and treatment of hyperuricemia in children with leukemia, lymphoma, and solid tumors. Prior to approval, 682 children and 387 adults in the US and Canada received rasburicase on compassionate-use basis. Uric acid concentration declined rapidly in both adult and pediatric patients after rasburicase treatment. Similar responses were observed in patients treated with subsequent courses. Possible drug-related adverse events, including allergic reactions, were uncommon. These data confirm that rasburicase is effective and safe for the treatment and prophylaxis of children and adults with malignancy-associated hyperuricemia.
Assuntos
Neoplasias Hematológicas/complicações , Hiperuricemia/tratamento farmacológico , Urato Oxidase/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Hiperuricemia/etiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Urato Oxidase/efeitos adversosRESUMO
Treatment options for persons with leukemia relapsing after allogeneic transplantation are limited. We analyzed the outcome of 279 patients with acute and chronic leukemia, who relapsed after HLA-identical sibling transplantation and received a second allogeneic transplant. The influence of potential risk factors on treatment-related mortality (TRM), relapse, treatment failure (relapse or death) and overall survival after second transplantation were assessed using proportional-hazards regression. The cumulative incidences (95% confidence interval) of relapse and TRM at 5 years were 42 (36-48)% and 30 (24-36)%, respectively. The 5-year probabilities of both overall and leukemia-free survival were 28 (23-34)%. In multivariate analyses, risks of treatment failure and mortality were lower in younger patients (< or =20 years) and patients who relapsed after 6 months from first transplantation. Risks of relapse were lower in patients who relapsed after 6 months from first transplantation and in complete remission prior to second transplantation. Risks of relapse were higher after reduced-intensity conditioning regimens. Any potential advantage of using a different matched related donor for a second transplantation is not supported by these data. Although age, disease status and conditioning regimen are important, duration of remission after first transplantation appear to be the most important determinant of outcome.
Assuntos
Transplante de Medula Óssea/métodos , Leucemia/terapia , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Criança , Família , Feminino , Doença Enxerto-Hospedeiro , Células-Tronco Hematopoéticas/citologia , Teste de Histocompatibilidade , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/terapia , Modelos Lineares , Masculino , Análise Multivariada , Neutrófilos/metabolismo , Contagem de Plaquetas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Risco , Fatores de Risco , Fatores Sexuais , Irmãos , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Fatores de Tempo , Transplante Homólogo , Resultado do TratamentoRESUMO
INTRODUCTION: Mercaptopurine is an important antimetabolite for treatment of childhood acute lymphoblastic leukemia (ALL). It has been prescribed to be given daily without therapeutic monitoring of drug levels. After first-pass metabolism by hepatic xanthine oxidase (XO), mercaptopurine is converted into two major intracellular metabolites, thioguanine nucleotide (TGN) and methylated mercaptopurine metabolites (including methylated thioinosine nucleotides), which are cytotoxic in vitro. Its short plasma half-life and S-phase-dependent pharmacokinetics suggest that biologically active concentration and exposure duration may be critical to cell kill. METHODS: Pediatric Oncology Group (POG) 9605, a randomized, open label phase III study of standard-risk ALL, was designed to compare daily with twice-daily mercaptopurine during continuation therapy. Red blood cell (RBC) TGN and methylated mercaptopurine metabolite levels were measured as surrogates of leukemic cell levels in a randomly selected subset of patients. TGN and methylated mercaptopurine metabolites were analyzed quantitatively by high-performance liquid chromatography (HPLC) and reported in ng/8 x 10.8 RBC. Statistical inferences utilized multiple linear regression. RESULTS: One hundred eighteen patients received mercaptopurine 75 mg/m(2) daily and 108 received 37.5 mg/m(2)/dose twice daily. Descriptive statistics for the daily group showed the median TGN was 42 ng (mean and standard deviation [SD] = 48 +/- 35, quartiles 29-64). For the twice daily group, it was 40 ng (mean and SD = 40 +/- 27, quartiles 26-53). For methylated mercaptopurine metabolites, the daily group median was 2,020 ng (mean and SD = 2,278 +/- 1,559, quartiles 1,247-3,162); the twice daily group median was 1,275 ng (mean and SD = 1,580 +/- 1,240, quartiles 599-2,369). When adjusted for the covariables: actual dosage, days on study, age at diagnosis, white blood cell count, gender, Black race compared with not, and Hispanic compared with not, daily dosing resulted in significantly higher average methylated mercaptopurine metabolites by 668 (standard error [SE] = 179, P = 0.001) and a trend toward higher average TGNs by 6.2 (SE = 4.2, P = 0.14). CONCLUSIONS: Daily dosing of mercaptopurine resulted in higher mean red cell methylated mercaptopurine metabolites when compared to split (twice a day dosing). The data were inconclusive with respect to TGNs. The relationships of methylated mercaptopurine metabolites and TGNs to clinical outcomes will be elucidated as part of the maturing 9605 data.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Mercaptopurina/administração & dosagem , Mercaptopurina/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Administração Oral , Disponibilidade Biológica , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Masculino , Mercaptopurina/análogos & derivados , Análise Multivariada , Análise de RegressãoRESUMO
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.
Assuntos
Aberrações Cromossômicas , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Quebra Cromossômica , Deleção Cromossômica , Análise Citogenética , Intervalo Livre de Doença , Feminino , Heterogeneidade Genética , Humanos , Funções Verossimilhança , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P=0.001) and L-asparaginase (L-ASP) (12-fold, P=0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P=0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, P<0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (<1 year, n=32, vs >/=1 year, n=19), nor within the MLL-rearranged ALL (<1 year, n=34, vs >/=1 year, n=8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (>7.4-fold, P=0.033) and 4-HOO-ifosfamide (4.4-fold, P=0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos , Rearranjo Gênico , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proto-Oncogenes , Fatores de Transcrição , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Distribuição por Idade , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Técnicas In Vitro , Lactente , Recém-Nascido , Masculino , Proteína de Leucina Linfoide-Mieloide , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismoRESUMO
Post-transplant lymphoproliferative disorders (PTLD) are morphologically/clinically heterogeneous. The main goal of this study was to define the histogenesis of PTLD (B-cell phenotype, EBV-related) in seven pediatric patients after allogeneic T-cell-depleted bone marrow transplantation. Immunohistochemical stains using histogenetic markers, including Bcl-6 (expressed by germinal center (GC) B cells), MUM1/IFR4 (late GC and post GC B cells), and CD138 (post GC B cells), were performed on paraffin-embedded tissue. By morphology, four cases were classified as polymorphic PTLD and three as monomorphic PTLD, according to the WHO classification. By the expression pattern of histogenetic markers, five cases (two polymorphic, three monomorphic PTLD) were of late GC/early post GC B-cell origin expressing only MUM1/IRF4. The remaining two cases (one monomorphic, one polymorphic PTLD) were of post GC B-cell origin expressing MUM1/IRF4 and CD138, but not Bcl-6. Our study indicates that histogenesis of PTLD may be defined by histogenetic markers using immunohistochemistry. The results suggest that most pediatric PTLD are of late GC/early post GC B-cell origin, and a minor group is of post GC B-cell origin. The histogenesis of PTLD appears independent of morphologic appearance. Further studies are warranted to confirm our observation and to evaluate the clinical significance of histogenetic pattern of PTLD.
Assuntos
Linfócitos B/patologia , Transplante de Medula Óssea/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Adolescente , Linfócitos B/virologia , Criança , Proteínas de Ligação a DNA/análise , Infecções por Vírus Epstein-Barr , Feminino , Centro Germinativo/patologia , Doenças Hematológicas/complicações , Doenças Hematológicas/terapia , Humanos , Imuno-Histoquímica , Fatores Reguladores de Interferon , Depleção Linfocítica , Transtornos Linfoproliferativos/classificação , Masculino , Glicoproteínas de Membrana/análise , Proteoglicanas/análise , Proteínas Proto-Oncogênicas/análise , Proteínas Proto-Oncogênicas c-bcl-6 , Sindecana-1 , Sindecanas , Fatores de Transcrição/análise , Transplante HomólogoRESUMO
Minimal residual disease (MRD) can be detected in the marrows of children undergoing chemotherapy either by flow cytometry or polymerase chain reaction. In this study, we used four-color flow cytometry to detect MRD in 1016 children undergoing therapy on Children's Oncology Group therapeutic protocols for precursor-B-cell ALL. Compliance was excellent, with follow-up samples received at the end of induction on nearly 95% of cases; sensitivity of detection at this time point was at least 1/10,000 in more than 90% of cases. Overall, 28.6% of patients had detectable MRD at the end of induction. Patients with M3 marrows at day 8 were much more likely to be MRD positive (MRD+) than those with M2 or M1 marrows. Different genetically defined groups of patients varied in their prevalence of MRD. Specifically, almost all patients with BCR-ABL had high levels of end-of-induction MRD. Only 8.4% of patients with TEL-AML1 were MRD+>0.01% compared with 20.3% of patients with trisomies of chromosomes 4 and 10. Our results show that MRD correlates with conventional measures of slow early response. However, the high frequency of MRD positivity in favorable trisomy patients suggests that the clinical significance of MRD positivity at the end of induction may not be the same in all patient groups.