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1.
Haematologica ; 104(8): 1617-1625, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30655366

RESUMO

The prognostic implications of DNMT3A genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute lymphoblastic leukemia patients with DNMT3A mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had DNMT3A alterations. Two patients also had DNMT3A mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia. DNMT3A mutation was associated with older age (median 43.9 years vs 29.4 years, P<0.001), immature T-cell receptor genotype (53.3% vs 24.4%, P=0.016) and lower remission rates (72.2% mutated vs 94.4% non-mutated, P=0.006). DNMT3A alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (HR 2.33, 95% CI: 1.05-5.16, P=0.037) and markedly poorer event-free survival (HR 3.22, 95% CI: 1.81-5.72, P<0.001) and overall survival (HR 2.91, 95% CI: 1.56-5.43, P=0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of DNMT3A-mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, DNMT3A mutation was significantly associated with shorter event-free survival (HR 2.33, 95% CI: 1.06 - 4.04, P=0.02). Altogether, these results identify DNMT3A genotype as a predictor of aggressive T-cell acute lymphoblastic leukemia biology. The GRAALL-2003 and -2005 studies were registered at http://www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678, respectively.

3.
J Clin Oncol ; 36(24): 2514-2523, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-29863974

RESUMO

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

5.
Blood ; 130(16): 1832-1844, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-28790105

RESUMO

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/KMT2A-AFF1 and 14q32/IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.


Assuntos
Aberrações Cromossômicas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Aberrações Cromossômicas/estatística & dados numéricos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise Citogenética , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Adulto Jovem
6.
J Clin Oncol ; 35(23): 2683-2691, 2017 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-28605290

RESUMO

Purpose Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL) is an immunophenotypically defined subgroup of T-cell ALL (T-ALL) associated with high rates of intrinsic treatment resistance. Studies in children have shown that the negative prognostic impact of chemotherapy resistance is abrogated by the implementation of early response-based intensification strategies. Comparable data in adults are lacking. Patients and Methods We performed comprehensive clinicobiologic, genetic, and survival analyses of a large cohort of 213 adult patients with T-ALL, including 47 patients with ETP-ALL, treated in the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia) -2003 and -2005 studies. Results Targeted next-generation sequencing revealed that the genotype of immunophenotypically defined adult T-ALL is similar to the pediatric equivalent, with high rates of mutations in factors involved in cytokine receptor and RAS signaling (62.2%), hematopoietic development (29.7%), and chemical modification of histones (48.6%). In contrast to pediatric cases, mutations in DNA methylation factor genes were also common (32.4%). We found that despite expected high levels of early bone marrow chemotherapy resistance (87%), the overall prognosis for adults with ETP-ALL treated using the GRAALL protocols was not inferior to that of the non-ETP-ALL group (5-year overall survival: ETP, 59.6%; 95% CI, 44.2% to 72.0% v non-ETP, 66.5%; 95% CI, 58.7% to 73.2%; P = 0.33) and that allogeneic stem-cell transplantation had a beneficial effect in a large proportion of patients with ETP-ALL. Conclusion Our results suggest that the use of response-based risk stratification and therapy intensification abrogates the poor prognosis of adult ETP-ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Neoplasias do Timo/genética , Neoplasias do Timo/terapia , Adulto , Ciclofosfamida/administração & dosagem , Metilação de DNA/genética , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos , Feminino , Genótipo , Hematopoese/genética , Histonas/química , Humanos , Imunofenotipagem , Masculino , Prognóstico , Receptores de Citocinas/genética , Transdução de Sinais/genética , Taxa de Sobrevida , Transplante Homólogo , Proteínas ras/genética , Proteínas ras/metabolismo
7.
Leuk Lymphoma ; 58(3): 586-593, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27397551

RESUMO

Little data have been published concerning invasive fungal infections during treatment of acute lymphoblastic leukemia (ALL). Patients included between May 2006 and October 2012 in the multicenter phase III trial for newly diagnosed ALL (GRAALL-2005) were retrospectively reviewed for the occurrence of IFI using the EORTC modified criteria. These patients did not routinely receive antifungal prophylaxis. Among 969 patients included (median age 47 years), 65 (6.7%) developed IFI during induction chemotherapy: 26 (3.3%) invasive aspergillosis (IA), 33 (3.4%) invasive candidiasis (IC) and six other IFI. For IA, the median time between induction therapy and IA diagnosis was 20 days. Diagnosis was probable in 22 cases and proven in four. Aspergillus antigen in serum was tested in all cases and positive in 24. Overall 12-week mortality after diagnosis of IA was 5/26 and attributable mortality related to the infection was 4/26 (15.4%). For IC, the median time between induction therapy and diagnosis was 19 days. Diagnosis was proven in 29 episodes. Candida albicans was the major pathogen in yeast infections (16/27). Overall 12-week mortality after diagnosis of IC was 8/33 (24.2%) and attributable mortality related to the infection was 7/33. The median delay between induction chemotherapy initiation and attributable death related to IC was 15 days. These findings may help to optimize the future management of ALL patients, and as in AML advocate systematic monitoring and the development of prophylactic or preemptive antifungal treatments.


Assuntos
Quimioterapia de Indução/efeitos adversos , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Adulto , Antifúngicos/uso terapêutico , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergilose/epidemiologia , Aspergilose/etiologia , Candidíase Invasiva/diagnóstico , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/epidemiologia , Candidíase Invasiva/etiologia , Ensaios Clínicos Fase III como Assunto , Feminino , França/epidemiologia , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
8.
N Engl J Med ; 375(11): 1044-53, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27626518

RESUMO

BACKGROUND: Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. METHODS: We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. RESULTS: From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. CONCLUSIONS: Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Adulto , Antígenos CD20/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Prognóstico , Indução de Remissão , Rituximab/efeitos adversos , Adulto Jovem
9.
Am J Hematol ; 90(11): 986-91, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26214580

RESUMO

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4).


Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Adolescente , Adulto , Antitrombinas/sangue , Veias Cerebrais/efeitos dos fármacos , Veias Cerebrais/patologia , Esquema de Medicação , Feminino , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Trombose Venosa/etiologia , Trombose Venosa/mortalidade , Trombose Venosa/patologia
10.
Blood ; 125(24): 3711-9, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-25878120

RESUMO

In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/uso terapêutico , Cromossomo Filadélfia , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Benzamidas/administração & dosagem , Benzamidas/toxicidade , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/toxicidade , Pirimidinas/administração & dosagem , Pirimidinas/toxicidade , Transplante de Células-Tronco , Resultado do Tratamento , Adulto Jovem
11.
Blood ; 125(16): 2486-96; quiz 2586, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25587040

RESUMO

Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.


Assuntos
Ensaios Clínicos como Assunto , Avaliação de Resultados (Cuidados de Saúde)/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Indução de Remissão , Transplante Homólogo , Adulto Jovem
12.
Blood ; 123(24): 3739-49, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24740809

RESUMO

With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.


Assuntos
Biomarcadores Tumorais/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
13.
J Clin Oncol ; 31(34): 4333-42, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24166518

RESUMO

PURPOSE: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. PATIENTS AND METHODS: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). RESULTS: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). CONCLUSION: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.


Assuntos
Proteínas de Ciclo Celular/genética , Análise Mutacional de DNA , Proteínas F-Box/genética , GTP Fosfo-Hidrolases/genética , Deleção de Genes , Proteínas de Membrana/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligases/genética , Proteínas ras/genética , Adulto , Intervalo Livre de Doença , Proteína 7 com Repetições F-Box-WD , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras) , Fatores de Risco , Fatores de Tempo , Adulto Jovem
15.
Blood ; 118(19): 5099-107, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21835957

RESUMO

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B(low)) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B(low) in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B(low) and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/genética , Mutação , Proteínas de Neoplasias/genética , Receptor Notch1/genética , Transativadores/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Criança , Protocolos Clínicos , Intervalo Livre de Doença , Proteína 7 com Repetições F-Box-WD , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia-Linfoma de Células T do Adulto/classificação , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Regulador Transcricional ERG , Resultado do Tratamento , Adulto Jovem
16.
J Clin Oncol ; 27(6): 911-8, 2009 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-19124805

RESUMO

PURPOSE: Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years. PATIENTS AND METHODS: Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome-negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. RESULTS: were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience. CONCLUSION: These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
17.
Leuk Res ; 32(11): 1741-50, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18508120

RESUMO

Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.


Assuntos
Neoplasias do Sistema Nervoso Central/etiologia , Recidiva Local de Neoplasia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/patologia , Terapia Combinada , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Indução de Remissão , Transplante de Células-Tronco , Resultado do Tratamento
18.
Cancer ; 110(12): 2747-55, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17963265

RESUMO

BACKGROUND: Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL. METHODS: The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years. RESULTS: By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months. CONCLUSIONS: The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk.


Assuntos
Segunda Neoplasia Primária/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Ensaios Clínicos como Assunto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
19.
Cancer ; 109(10): 2058-67, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17407135

RESUMO

BACKGROUND: In adult acute lymphoblastic leukemia, treatment results generally are expressed in terms of overall survival or disease-free survival at 3 years. In this investigation, the authors attempted to express the results in terms of the proportion of long-term disease-free survivors and in terms of lifetime in patients who developed recurrent disease or died. METHODS: Univariate and multivariate analyses were used to assess the influence of different covariates on the 2 result criteria in 922 participants in the Adult Acute Lymphoblastic Leukemia-94 multicenter trial. RESULTS: The proportion of long-term survivors was 21.5% (95% confidence interval [95% CI], 18.1-25.4%) and was higher in women than in men. The proportion decreased with increasing age, white blood cell count, and lactate dehydrogenase level. The lowest proportion was observed in patients ages 44 years to 55 years (11.4%; 95% CI, 7-17.9%) and in patients with the t(9;22) BCR-ABL karyotype (13.4%; 95% CI, 8.8-19.8%), and the highest proportion was observed in patients with the t(4;11) MLL-AF4 karyotype (31.3%; 95% CI, 18.2-48.3%). The mean expected lifetime of patients who were not cured was 11.4 months (95% CI, 9.1-14.1 months). It was longer in men than in women and was shorter with increasing age, performance status, hemoglobin level, and white blood cell count. CONCLUSIONS: The results of this study highlighted and specified the importance of some classic prognostic factors in patients with acute lymphoblastic leukemia.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Genes abl/genética , Humanos , Cariotipagem , L-Lactato Desidrogenase/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Razão de Chances , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Falha de Tratamento
20.
Blood ; 109(4): 1408-13, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17062730

RESUMO

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomo Filadélfia , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Adolescente , Adulto , Benzamidas , Citarabina/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Análise de Sobrevida , Transplante Homólogo
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