RESUMO
Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers. Most cancers, however, contain multiple genetic alterations belonging to and of various hallmarks of cancer; for most of these alterations, there is limited knowledge on the level of evidence, their hierarchical roles in oncogenicity, and utility as biomarkers for response to targeted treatment(s). We developed a proof-of-concept trial that explores new treatment strategies in a molecularly-enriched tumor-agnostic, pediatric population. The evaluation of novel agents, including first-in-child molecules, alone or in combination, is guided by the available understanding of or hypotheses for the mechanisms of action of the diverse cancer events. Main objectives are: to determine 1) recommended phase 2 doses, 2) activity signals to provide the basis for disease specific development, and 3) to define new predictive biomarkers. Here we outline concepts, rationales and designs applied in the European AcSé-ESMART trial and highlight the feasibility but also complexity and challenges of such innovative platform trials.
Assuntos
Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Biomarcadores Tumorais/genética , Terapia de Alvo Molecular/métodos , Projetos de Pesquisa/normas , Ensaios Clínicos Fase II como Assunto , Estudo de Prova de ConceitoAssuntos
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Ensaios Clínicos como AssuntoRESUMO
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.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Ciclofosfamida/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidadeRESUMO
Patients with cancers of differing histologies that express certain biomarkers are likely to benefit from treatment with targeted therapies. However, targets can be present in malignancies other than those indicated by a drug's label, and as a result, affected patients will have no access to those potentially useful drugs. To tackle this issue, the French National Cancer Institute developed the AcSé Programme in 2013. This programme is designed to make treatment decisions or recommendations on the basis of the presence of relevant biomarkers for malignancies with no targeted therapies available and also aims to improve safety, and evaluate the efficacy of targeted drugs used outside of their approved indications. Patients across France have access to molecular testing in 28 molecular genetics centres and to targeted therapies within phase II trials provided no other trials exist in which they could reasonably be included. Trials include patients below the age of 18 if safe dosing data are available. As of January 2016, 183 French clinical sites and over 7,000 patients are participating in AcSé led trials. Proof of concept is being demonstrated through trials designed to investigate the effectiveness of crizotinib and vemurafenib in a wide variety of cancers.
Assuntos
Neoplasias/terapia , Medicina de Precisão/normas , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto , Crizotinibe , Acessibilidade aos Serviços de Saúde , Humanos , Indóis/uso terapêutico , Neoplasias/genética , Uso Off-Label , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Sulfonamidas/uso terapêutico , VemurafenibRESUMO
RATIONALE: Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects. OBJECTIVES: To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT. METHODS: In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account. MEASUREMENTS AND MAIN RESULTS: At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty-five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment. CONCLUSIONS: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).
Assuntos
Bronquiolite Obliterante/terapia , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Etanolaminas/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Complicações Pós-Operatórias/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Fumarato de Formoterol , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
Because the indication of allograft (allogeneic stem cell transplantation [alloSCT]) for multiple myeloma (MM) has widened in recent years, thanks to the development of reduced-intensity conditionings (RIC), it is still unclear if myeloablative conditioning (MAC) remains appropriate. This study compares retrospectively outcomes of patients undergoing either RIC or MAC regimens for MM. Based on the SFGM-TC registry, we included 446 MM patients receiving alloSCT between 1999 and 2009 for whom a minimal data set was available. Median follow-up for the entire cohort was 33.6 months (range, 0 to 164.5). RIC and MAC populations were different regarding age (53.5 versus 47.1 years, respectively), number of prior autologous (auto)SCTs (93.2% versus 79.6% had at least 2 autoSCTs), and stem cell source (90.2% versus 61.2% received peripheral blood). For RIC and MAC populations the nonrelapse mortality at 2 years was 24.6% and 22.4%, respectively, progression-free survival 35.5% and 51.1%, and overall survival 59.5% and 66.7% (not significant). These outcomes were not affected by conditioning intensity either on univariate or multivariate analysis. Despite some limitations in the study design, these results indicate that MAC should remain a valuable option in alloSCT for MM, especially for young and less-treated patient with no comorbidity. The constant progress in induction treatments of MM and supportive care after alloSCT could improve these results in the near future.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: French national cancer plans were rolled out oncogeriatric coordination units in France in particular to enable all elderly people with cancer in each region to benefit from a specific care management. METHODS: The national hospital discharge database was analyzed in order to analyze hospitalizations related to cancer care in ≥75 years patients for year 2012. RESULTS: A total of 358,721 patients with 1,492,935 hospitalizations were recorded, respectively with chemotherapy (32.4%), radiotherapy (23.0%), surgery (10.6%), palliative care (3.9%), or other care (30.9%). Hospital activity was distributed in hospitals (36.3%), clinics (23.4%), academic hospitals (20.9%), cancer centers (11.8%). Their respective share varied according to care. Total activity volume and number of health care facilities involved were highly variable in the different regions. CONCLUSION: These data would permit development of a national oncogeriatric policy through the action of regional oncogeriatric coordination units. These units should prioritize training actions and good practice guidelines dissemination in health care institutions with a high activity volume in this domain.
Assuntos
Hospitalização/estatística & dados numéricos , Neoplasias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Institutos de Câncer/estatística & dados numéricos , Feminino , França/epidemiologia , Hospitais/estatística & dados numéricos , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/terapia , Cuidados Paliativos/estatística & dados numéricos , Radioterapia/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricosRESUMO
A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m(2)). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 10(7)/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (<3.4 × 10(7)/kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence (P = .04). Leukemia-free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML (P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67).
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Doadores não Relacionados , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal TotalRESUMO
BACKGROUND: The purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry. METHODS: Among 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations. RESULTS: Median age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn's disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate. The bone marrow smears exhibited mild late-stage granulopoeitic defects. One patient developed myelodysplasia followed by acute myelogenous leukemia with translocation (18, 21) at age 14 years, cured by chemotherapy and hematopoietic stem cell transplantation. Four deaths occurred, including one from sepsis at age 5, one from pulmonary late-stage insufficiency at age 19, and two from sudden death, both at age 30 years. A new homozygous mutation (c.249G > A /p.Trp83*) was detected in one pedigree. CONCLUSIONS: Severe congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia.
Assuntos
Glucose-6-Fosfatase/genética , Mutação/genética , Neutropenia/congênito , Sistema de Registros , Adulto , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Seguimentos , França/epidemiologia , Humanos , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/mortalidade , Linhagem , Taxa de Sobrevida/tendências , Adulto JovemRESUMO
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 JovemRESUMO
UNLABELLED: Measuring waiting times is a good indicator of quality of cancer care and could reveal inequalities in cancer care access. AIMS: To determine the most representative waiting times in breast, lung, colon and prostate cancer care in several regions of France. To analyze the influence of individual, medical or health care system factors on those waiting times. METHODS: This study was piloted by the French Cancer Institute in partnership with the National Federation of the Regional Health Observatories and was driven by the Regional Oncology Networks and the Regional Health Observatories. In 2011, 2,530 women with breast cancer and 1,945 patient with lung cancer were included in eight regions, and in 2012, 3,248 patients with colon cancer and 4,207 men with prostate cancer were included in 13 regions, two of which were overseas departments. Data were analyzed from multidisciplinary discussion reports and from medical records. RESULTS: The mean time intervals (± standard deviation) for the various components of access to care were as follows in breast cancer: mammography to pathologist diagnosis, 17,7 days (±15,9); diagnosis (or treatment proposal) to surgery, 22,9 days (±13,9). In lung cancer: first suspect medical image to pathologist diagnosis, 21,5 days (±17,6); diagnosis to treatment proposal, 13,5 days (±10,7). In colon cancer: coloscopy to pathologist diagnosis, 4,5 days (±4,1); diagnosis to surgery, 18,9 days (±14,9). In prostate cancer: pathologist diagnosis to treatment proposal, 36,5 days (±26,5); treatment proposal to surgery, 45,2 days (±30,1). Data collection was particularly difficult because of very heterogeneous way in medical records filling by care centers, so the data collection method used in the study could not be used in routine procedures. Waiting times measured in the four cancers had an important variability. In fact, age, circumstance of diagnosis, tumor stage and category of care center had an influence. After considering those different factors, differences between regions remained from range 2 to 4. Those regional differences could be explained by organizational factors but were not explored in our study. In the same way, data on individual factors (social vulnerability, category of employment) were not available to measure their effects on this study. Besides, our results were comparable to those in international publications or national recommendations in other countries. CONCLUSION: These results suggest that waiting times could be good indicators and could reveal inequalities in cancer care access. Measuring them would lead to characterize those inequalities and to propose actions to improve access to cancer care whose impact could be measured.
Assuntos
Neoplasias da Mama/terapia , Neoplasias do Colo/terapia , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Neoplasias Pulmonares/terapia , Neoplasias da Próstata/terapia , Qualidade da Assistência à Saúde/estatística & dados numéricos , Listas de Espera , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/epidemiologia , Feminino , França/epidemiologia , Acessibilidade aos Serviços de Saúde/normas , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Qualidade da Assistência à Saúde/normas , Programas Médicos Regionais/normas , Programas Médicos Regionais/estatística & dados numéricos , Fatores de Tempo , Tempo para o Tratamento/estatística & dados numéricosRESUMO
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 JovemAssuntos
Prestação Integrada de Cuidados de Saúde/organização & administração , Neoplasias/prevenção & controle , Academias e Institutos/organização & administração , Pesquisa Biomédica/métodos , Difusão de Inovações , França , Implementação de Plano de Saúde , Disparidades em Assistência à Saúde , Humanos , Oncologia/organização & administração , Terapia de Alvo Molecular , Objetivos Organizacionais , Qualidade de Vida , Pesquisa Translacional BiomédicaRESUMO
Allogeneic hematopoietic stem cell (HSC) transplantation is a curative treatment for many hematologic malignancies for which umbilical cord blood (UCB) represents an alternative source of HSCs. To overcome the low cellularity of one UCB unit, double UCB transplantation (dUCBT) has been developed in adults. We have analyzed the outcome of 136 patients who underwent dUCBT reported to the SFGM-TC registry between 2005 and 2007. Forty-six patients received myeloablative regimens, and 90 patients received reduced-intensity conditioning regimens. There were 84 cases of leukemia, 17 cases of non-Hodgkin lymphoma, 11 cases of myeloma, and 24 other hematologic malignancies. At transplantation, 40 (29%) patients were in complete remission. At day 60 after transplantation, the cumulative incidence of neutrophil recovery was 91%. We observed one UCB unit domination in 88% of cases. The cumulative incidence of day 100 acute graft-versus-host disease, chronic graft-versus-host disease, transplant-related mortality, and relapse at 2 years were 36%, 23%, 27%, and 28% respectively. After a median follow-up of 49.5 months, the 3-year probabilities of overall and progression-free survival were 41% and 35%, respectively, with a significant overall survival advantage when male cord engrafted male recipients. We obtained a long-term plateau among patients in complete remission, which makes dUCBT a promising treatment strategy for these patients.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Neoplasias Hematológicas/cirurgia , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
The incidence of cancer will increase dramatically among elderly people in the 21st century. The first French National Cancer Plan (2003-2006) with the French Ministry of Health supported the creation of 15 pilot coordination units in oncogeriatrics (UPCOG) in 13 out of the 27 French regions. The second French National Cancer Plan (2009-2013) continues to support oncogeriatrics. Based on evaluation of the pilot experiment in 2010, requirement specifications for an oncogeriatric coordination unit were defined and rolled out nationwide. The following missions were set out: to adjust cancer treatment in elderly people and enable all elderly cancer patients to benefit from this oncogeriatric approach; to stimulate specific research in oncogeriatrics; to promote training of health professionals, and to promote information. The clinical use of a geriatric prescreening tool as a routine procedure needs to become more widespread. Lastly, recommendations for treatment strategies tailored to elderly persons with high-incidence cancer must be developed. Fifteen oncogeriatrics coordination units were founded since 2011, covering 11 regions. Roll-out continues in 2012.
Assuntos
Atenção à Saúde , Geriatria , Oncologia , Neoplasias , Equipe de Assistência ao Paciente , Idoso , Pesquisa Biomédica/organização & administração , Procedimentos Clínicos/normas , Procedimentos Clínicos/tendências , Atenção à Saúde/métodos , Atenção à Saúde/organização & administração , Previsões , França/epidemiologia , Geriatria/métodos , Geriatria/organização & administração , Necessidades e Demandas de Serviços de Saúde , Humanos , Oncologia/métodos , Oncologia/organização & administração , Programas Nacionais de Saúde , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapia , Equipe de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/tendências , Projetos PilotoRESUMO
Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graft-versus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T- and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P = .003) and after a reduced-intensity conditioning regimen (P = .03). Low posttransplantation iNKT/T ratios (ie, < 10(-3)) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P = .001). Inversely, reaching iNKT/T ratios > 10(-3) before day 90 was associated with reduced nonrelapse mortality (P = .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P = .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 × 10(-3) was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Células T Matadoras Naturais/imunologia , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Fatores Etários , Feminino , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Efeito Enxerto vs Leucemia/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Recidiva , Fatores de Risco , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/patologia , Fatores de Tempo , Doadores de Tecidos , Transplante HomólogoRESUMO
This retrospective multicenter report assessed the outcome of 600 patients with hematologic diseases older than 60 years who received reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT), with the specific aim to compare outcomes of patients between 60 and 65 years old (N = 493) with those older than 65 years (N = 107). Except for donor age, there were no significant differences between the groups regarding patients, diseases, and allo-HSCT characteristics. At time of RIC allo-HSCT, 276 patients (46%) were in complete remission. With a median follow-up of 22.8 and 23.7 months in the younger and the older groups, respectively, 2-year relapse, nonrelapse mortality, disease-free survival, and overall survival rates were similar in both groups (29.6% vs. 20.4%; 29.9% vs. 34.6%; 40.6% vs. 46.7%; 49.2% vs. 50.2%, respectively; P = NS for all comparisons). In a Cox multivariate analysis, after adjustment for disease and transplant factors, age per se was not an adverse factor for survival (relative risk = 1.08; 95% confidence interval, 0.81-1.44, P = .62). We conclude that in selected patients, RIC allo-HSCT could be offered to patients over 65 years old.
Assuntos
Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Fatores Etários , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Doadores de Tecidos , Transplante HomólogoRESUMO
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 JovemRESUMO
BACKGROUND: The impact of cytogenetic abnormalities in multiple myeloma after allogeneic stem cell transplantation has not been clearly defined. This study examines whether allogeneic stem cell transplantation could be of benefit for myeloma patients with high-risk cytogenetic abnormalities. DESIGN AND METHODS: This is a retrospective multicenter analysis of the registry of the Société Française de Greffe de Moelle et de Thérapie Cellulaire, including 143 myeloma patients transplanted between 1999 and 2008. RESULTS: The incidences of cytogenetic abnormalities were 59% for del(13q), 25% for t(4;14), 25% for del(17p) and 4% for t(14;16). When comparing the population carrying an abnormality to that without the same abnormality, no significant difference was found in progression-free survival, overall survival or progression rate. Patients were grouped according to the presence of any of the poor prognosis cytogenetic abnormalities t(4;14), del(17p) or t(14;16) (n=53) or their absence (n=32). No difference in outcomes was observed between these two groups: the 3-year progression-free survival, overall survival and progression rates were 30% versus 17% (P=0.9), 45% versus 39% (P=0.8) and 53% versus 75% (P=0.9), respectively. CONCLUSIONS: These data indicate that allogeneic stem cell transplantation could potentially be of benefit to high-risk myeloma patients.
Assuntos
Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Adulto , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Prognóstico , Estudos Retrospectivos , Transplante Homólogo , Resultado do TratamentoRESUMO
PURPOSE: To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT). PATIENTS AND METHODS: The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months. RESULTS: Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors. CONCLUSION: Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.