Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 114
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Ann Oncol ; 29(4): 973-978, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29390048

RESUMEN

Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Mitoxantrona/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/efectos adversos , Daunorrubicina/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitoxantrona/efectos adversos , Inducción de Remisión , Análisis de Supervivencia
2.
Ann Oncol ; 28(11): 2793-2798, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28945881

RESUMEN

BACKGROUND: The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1). PATIENTS AND METHODS: We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. The NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML subgroup comprised 497 patients, aged 18-60 years. RESULTS: In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3-0.9, P = 0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3-1.1, P = 0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37-0.9, P = 0.02) and relapse-free survival (HR 0.51, 95% CI 0.34-0.76; P = 0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer. CONCLUSION: Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate risk NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML in CR1. CINICALTRIALS.GOV IDENTIFIER: NCT00180115, NCT00180102.


Asunto(s)
Biomarcadores de Tumor/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Mutación , Proteínas Nucleares/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Nucleofosmina , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Trasplante Homólogo , Adulto Joven
3.
J R Soc Interface ; 17(170): 20200091, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32900301

RESUMEN

Disease response and durability of remission are very heterogeneous in patients with acute myeloid leukaemia (AML). There is increasing evidence that the individual risk of early relapse can be predicted based on the initial treatment response. However, it is unclear how such a correlation is linked to functional aspects of AML progression and treatment. We suggest a mathematical model in which leukaemia-initiating cells and normal/healthy haematopoietic stem and progenitor cells reversibly change between an active state characterized by proliferation and chemosensitivity and a quiescent state, in which the cells do not divide, but are also insensitive to chemotherapy. Applying this model to 275 molecular time courses of nucleophosmin 1-mutated patients, we conclude that the differential chemosensitivity of the leukaemia-initiating cells together with the cells' intrinsic proliferative capacity is sufficient to reproduce both, early relapse as well as long-lasting remission. We can, furthermore, show that the model parameters associated with individual chemosensitivity and proliferative advantage of the leukaemic cells are closely linked to the patients' time to relapse, while a reliable prediction based on early response only is not possible based on the currently available data. Although we demonstrate with our approach, that the complete response data is sufficient to quantify the aggressiveness of the disease, further investigations are necessary to study how an intensive early sampling strategy may prospectively improve risk assessment and help to optimize individual treatments.


Asunto(s)
Leucemia Mieloide Aguda , Recurrencia Local de Neoplasia , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Modelos Teóricos , Inducción de Remisión , Medición de Riesgo
4.
Biomol Detect Quantif ; 15: 6-12, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29349042

RESUMEN

Monitoring of minimal residual disease (MRD) has become an important clinical aspect for early relapse detection during follow-up care after cancer treatment. Still, the sensitive detection of single base pair point mutations via Next-Generation Sequencing (NGS) is hampered mainly due to high substitution error rates. We evaluated the use of NGS for the detection of low-level variants on an Ion Torrent PGM system. As a model case we used the c.1849G > T (p.Val617Phe) mutation of the JAK2-gene. Several reaction parameters (e.g. choice of DNA-polymerase) were evaluated and a comprehensive analysis of substitution errors was performed. Using optimized conditions, we reliably detected JAK2 c.1849G > T VAFs in the range of 0.01-0.0015% which, in combination with results obtained from clinical data, validated the feasibility of NGS-based MRD detection. Particularly, PCR-induced transitions (mainly G > A and C > T) were the major source of error, which could be significantly reduced by the application of proofreading enzymes. The integration of NGS results for several common point mutations in various oncogenes (i.e. IDH1 and 2, c-KIT, DNMT3A, NRAS, KRAS, BRAF) revealed that the prevalent transition vs. transversion bias (3.57:1) has an impact on site-specific detection limits of low-level mutations. These results may help to select suitable markers for MRD detection and to identify individual cut-offs for detection and quantification.

5.
Leukemia ; 20(4): 707-14, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16482208

RESUMEN

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22-74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n = 19) or inadequate blast clearance by induction chemotherapy (IC, n = 7). The median age was 49 years (range 17-68). During IC-induced aplasia after the 1st (n = 11) or 2nd (n = 15) cycle, patients received allogeneic peripheral blood stem cells (PBSC) from related (n = 11) or unrelated (n = 15) donors following a fludarabine-based reduced-intensity regimen. Seventeen patients were not in remission before HSCT with a median marrow blast count of 34% (range 6-70). All patients achieved rapid engraftment and went into remission with complete myeloid and lymphatic chimerism. Grades II to IV acute GvHD occurred in 14 (56%) and extensive chronic GvHD was documented in 8 (35%) patients. The probability of disease-free survival was 61% with only three patients relapsing 5, 6 and 7 months after transplantation, respectively. Up-front allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in high-risk AML patients and warrants further investigation.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide/terapia , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimerismo , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento
6.
Leukemia ; 20(3): 437-43, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16424870

RESUMEN

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Leucemia Mieloide/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Ácido Retinoico/metabolismo , Transducción de Señal , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Cromosomas Humanos Par 7 , Inhibidores Enzimáticos/farmacología , Femenino , Técnica del Anticuerpo Fluorescente , Inhibidores de Histona Desacetilasas , Humanos , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Receptores de Ácido Retinoico/antagonistas & inhibidores , Ácido Valproico/farmacología
7.
Leukemia ; 31(12): 2807-2814, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28443606

RESUMEN

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.


Asunto(s)
Variación Genética , Genotipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Aberraciones Cromosómicas , Cromosomas Humanos Par 7 , Ensayos Clínicos como Asunto , Femenino , Humanos , Cariotipo , Leucemia Mieloide Aguda/diagnóstico , Masculino , Monosomía , Mutación , Pronóstico , Análisis de Supervivencia
8.
Leukemia ; 31(11): 2347-2354, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28322237

RESUMEN

Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.


Asunto(s)
Arsenicales/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Óxidos/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trióxido de Arsénico , Femenino , Humanos , Leucemia Promielocítica Aguda/etiología , Leucemia Promielocítica Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/genética , Inducción de Remisión , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
9.
J Natl Cancer Inst ; 89(18): 1350-5, 1997 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-9308704

RESUMEN

BACKGROUND: Low-grade B-cell lymphomas arising in mucosa-associated lymphoid tissue (MALT) are most frequently localized in the gastrointestinal tract. More than 90% of gastric MALT lymphomas are diagnosed in patients with chronic, Helicobacter pylori-associated gastritis. High remission rates for these lymphomas have been observed after the cure of H. pylori infection. Data are lacking, however, with regard to the duration of the remissions. To address this question of remission duration, we have followed 50 patients in whom H. pylori infections were eradicated, and we determined whether the patients in complete remission displayed evidence of residual monoclonal B cells during follow-up. METHODS: Patients were treated with amoxycillin and omeprazole for 2 weeks in an attempt to cure H. pylori infections. Follow-up included endoscopic investigations with biopsy sampling. Monoclonal B cells in biopsy specimens were detected by means of a polymerase chain reaction (PCR)-based assay. RESULTS: H. pylori infections were cured in all 50 patients. The median follow-up for the 50 patients is currently 24 months (729 days; range, 135-1411 days). Forty patients achieved complete remission of their lymphomas, but five have subsequently relapsed. The median time of continuous complete remission for the 40 patients was 15.4 months (468 days; range, 0-1198 days). Among six patients whose Iymphomas did not respond to H. pylori eradication, four revealed high-grade lymphomas upon surgery. PCR indicated the presence of monoclonal B cells during follow-up in 22 of 31 assessable patients in complete remission. CONCLUSIONS: Complete remissions of low-grade gastric MALT Iymphomas after the cure of H. pylori infection appear to be stable, although most patients display evidence of monoclonal B cells during follow-up. Whether these patients are truly cured of their Iymphomas remains to be determined.


Asunto(s)
Gastritis/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Amoxicilina/uso terapéutico , Antiulcerosos/uso terapéutico , Supervivencia sin Enfermedad , Quimioterapia Combinada , Femenino , Gastritis/microbiología , Infecciones por Helicobacter/microbiología , Humanos , Linfoma de Células B de la Zona Marginal/microbiología , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neoplasia Residual , Omeprazol/uso terapéutico , Penicilinas/uso terapéutico , Reacción en Cadena de la Polimerasa , Inducción de Remisión , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del Tratamiento
10.
Leukemia ; 30(4): 782-8, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26582645

RESUMEN

Mutations in isocitrate dehydrogenases (IDHs) 1 and 2 frequently occur in acute myeloid leukemia (AML) and result in the production of the oncometabolite d-2-hydroxyglutarate (D2HG). D2HG has been shown to promote leukemogenesis even in the absence of mutated IDH, but the prognostic significance of pretreatment serum D2HG levels in patients with IDH-mutated AML is unclear. We measured D2HG serum levels in 84 patients with IDH-mutated AML treated in the prospective, randomized multicenter AML2003 trial of the German Study Alliance Leukemia. Multivariate Cox regression showed D2HG levels to negatively impact on event-free survival (EFS) as a continuous variable in the entire IDH(mut) cohort (P=0.04), with no effect on overall survival (OS). In a subgroup analysis, the negative impact of D2HG on EFS was found to be restricted to patients with mutations in IDH1 (P=0.003), adjusted for age, leukocyte count, serum lactate dehydrogenase and European LeukemiaNet risk score. We thus conclude that pretreatment D2HG serum levels may yield prognostic information in patients with IDH1-mutated, but not in IDH2-mutated AML, possibly due to different subcellular localizations of IDH1 and IDH2.


Asunto(s)
Biomarcadores de Tumor/sangre , Glutaratos/sangre , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/sangre , Mutación/genética , Adolescente , Adulto , Análisis Citogenético , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto Joven
11.
Blood Cancer J ; 6(7): e449, 2016 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-27471865

RESUMEN

The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.


Asunto(s)
Biomarcadores de Tumor , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Neoplasia Residual/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Anciano , Biomarcadores , Médula Ósea/patología , Femenino , Duplicación de Gen , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Neoplasia Residual/diagnóstico , Nucleofosmina , Cuidados Preoperatorios , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Secuencias Repetitivas de Ácidos Nucleicos , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genética
12.
Leukemia ; 30(2): 261-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26283567

RESUMEN

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.


Asunto(s)
Nucleótidos de Adenina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Terapia Recuperativa , Adulto , Anciano , Clofarabina , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Trasplante Homólogo
13.
Leukemia ; 30(6): 1237-45, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26847026

RESUMEN

Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.


Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Epigénesis Genética , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicos/metabolismo , Factores de Transcripción/biosíntesis , Acetilación , Animales , Carcinogénesis/genética , Proteínas de Unión al ADN/deficiencia , Progresión de la Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Histona Acetiltransferasas/antagonistas & inhibidores , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Síndromes Mielodisplásicos/genética , Proteínas de Fusión Oncogénica , Pronóstico , Factores de Transcripción/deficiencia
14.
Leukemia ; 30(3): 555-61, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26522083

RESUMEN

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/uso terapéutico , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Citarabina/uso terapéutico , Análisis Citogenético , Daunorrubicina/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Análisis de Supervivencia
15.
J Clin Oncol ; 19(7): 2041-8, 2001 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-11283137

RESUMEN

PURPOSE: Treatment of low-grade gastric mucosa-associated lymphoid tissue lymphoma by eradication of Helicobacter pylori is reported to result in complete lymphoma remission in approximately 75% of cases. The effect that cure of the infection has on the course of a primary high-grade gastric lymphoma is largely uncertain. The aim of this study was to report the effect of cure of H pylori infection exerted in patients with high-grade B-cell gastric lymphoma. PATIENTS AND METHODS: Eight patients (4 males and 4 females; age range, 26 to 85 years) with H pylori infection and high-grade lymphoma received eradication therapy before planned treatment. The effect of H pylori eradication on the course of high-grade lymphoma was assessed by analysis of surgical specimens (n = 2) or endoscopic biopsies (n = 6). RESULTS: H pylori eradication was successful in all patients and led to complete remission of the lymphoma in seven patients. One patient has experienced partial remission. Two patients were referred to surgery, one of whom (stage II(1E)) had lymph node involvement, and the histologic work-up of the resected stomach revealed residual infiltrates of a low-grade lymphoma, which prompted consolidation chemotherapy. In one patient (initially stage I(1E)), abdominal lymphoma developed 6 months after eradication therapy, which regressed completely after chemotherapy. In four patients, no further treatment was given. Six patients continue in complete remission (range, 6 to 66 months). CONCLUSION: Primary high-grade B-cell gastric lymphoma in stages I(E) through II(E1) associated with H pylori may regress completely after successful cure of the infection. Prospective trials are needed to investigate this treatment in larger numbers of patients.


Asunto(s)
Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Linfoma de Células B/microbiología , Linfoma no Hodgkin/microbiología , Neoplasias Gástricas/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Amoxicilina/uso terapéutico , Antiulcerosos/uso terapéutico , Transformación Celular Neoplásica , Femenino , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/microbiología , Linfoma de Células B de la Zona Marginal/patología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Omeprazol/uso terapéutico , Penicilinas/uso terapéutico , Inducción de Remisión/métodos , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología
16.
J Clin Oncol ; 19(6): 1600-9, 2001 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11250988

RESUMEN

PURPOSE: Cure of Helicobacter pylori infection is associated with remission induction in the majority of patients with low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma in localized stages; however, limited data exist as to whether these patients may be cured of their lymphoma. The present study was performed to investigate whether the polymerase chain reaction (PCR) for the rearranged immunoglobulin heavy chain region may be used to define "molecular" remission. PATIENTS AND METHODS: Ninety-seven patients who suffered from low-grade gastric MALT lymphoma stage I(E) were observed with central pathology and molecular biology after cure of H pylori infection. PCR was performed with the use of consensus primers for the framework regions 1, 2, and 3 and monoclonality was corroborated by sequence analysis. In selected cases, microdissection was performed to study the origin of the monoclonal B cells. RESULTS: Of the 97 patients, 77 obtained complete endoscopic and histologic remission (CR). Twenty of 44 patients with PCR monoclonality at diagnosis and with sufficient molecular follow-up displayed monoclonal bands for a median time of 20.5 months after CR (range, 0 to 50.4 months). These B cells were related to the original lymphoma clone by sequence analysis. Microdissection analysis identified basal lymphoid aggregates as the source of these monoclonal B cells. Local relapse occurred in and was observed by PCR in four patients. All four patients displayed monoclonal PCR before relapse, and three of these four showed ongoing PCR monoclonality throughout their course, indicating the persistence of malignant cells. CONCLUSION: Half of all patients with gastric MALT lymphoma show long-term PCR monoclonality up to several years after cure of H pylori infection and CR. Patients with monoclonal PCR should be observed closely, whereas long-term PCR negativity may indicate cure of the disease.


Asunto(s)
Linfocitos B/inmunología , ADN de Neoplasias/análisis , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/patogenicidad , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia Celular , Células Clonales , Femenino , Infecciones por Helicobacter/inmunología , Humanos , Linfoma de Células B de la Zona Marginal/inmunología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Prospectivos , Análisis de Secuencia de ADN , Resultado del Tratamiento
17.
J Clin Oncol ; 15(3): 1104-9, 1997 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9060551

RESUMEN

PURPOSE: The differential diagnosis of early gastric mucosa-associated lymphatic tissue (MALT) lymphoma based on Helicobacter pylori gastritis may be difficult when lymphoepithelial lesions are not detected. The aim of the present study was to investigate the question whether the polymerase chain reaction (PCR) or cure of H pylori infection may be of help in this respect. PATIENTS AND METHODS: Twenty patients with suspected low-grade gastric MALT lymphomas were treated in a double-blinded, randomized, crossover trial with 2,250 mg of either amoxicillin or placebo, both in combination with omeprazole, for 14 days with the aim to cure H pylori infection. PCR was performed using primers specific for the CDR3 region to detect monoclonal B cells. RESULTS: In five of 20 patients, MALT lymphomas were finally diagnosed. Three of these five patients went into complete remission, while two were referred to surgery. In the 15 patients with gastritis, complete regression was observed in all cases. With respect to PCR, monoclonal bands were detected in all four of the analyzed lymphoma patients before histology showed lymphoma. In addition, monoclonal bands were found in three patients with gastritis. In the patients with gastritis and monoclonal PCR, complete regression took longer as compared with the remaining 12 patients with polyclonal PCR and gastritis (P = .0209). Successful H pylori eradication was associated with earlier diagnosis of the MALT lymphoma (P = .0237). CONCLUSION: CDR3-PCR may be of help in the differential diagnosis of early gastric MALT lymphoma. Furthermore, H pylori eradication may lead to earlier diagnosis.


Asunto(s)
Gastritis/diagnóstico , Infecciones por Helicobacter/diagnóstico , Helicobacter pylori , Linfoma de Células B de la Zona Marginal/diagnóstico , Reacción en Cadena de la Polimerasa , Adulto , Anciano , Anciano de 80 o más Años , Amoxicilina/uso terapéutico , Antiulcerosos/uso terapéutico , Estudios Cruzados , Diagnóstico Diferencial , Método Doble Ciego , Femenino , Gastritis/complicaciones , Gastritis/tratamiento farmacológico , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Linfoma de Células B de la Zona Marginal/etiología , Linfoma de Células B de la Zona Marginal/microbiología , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Omeprazol/uso terapéutico , Penicilinas/uso terapéutico
18.
J Clin Oncol ; 16(12): 3822-31, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9850027

RESUMEN

PURPOSE: Although most patients with primary gastric low-grade mucosa-associated lymphoid tissue (MALT) B-cell lymphoma experience complete endoscopic and histologic remission after the cure of Helicobacter pylori infection, in many patients, the polymerase chain reaction (PCR) still detects monoclonal B cells in the gastric mucosa. The present study asked whether the lymphoma immunoglobulin VH (IgVH) sequences remained stable in patients with gastric MALT lymphoma after H pylori eradication. PATIENTS AND METHODS: Eight patients with stage EI disease treated with H pylori eradication were analyzed before and at different time points after the cure of the infection. After the amplification of IgVH genes from DNA extracted from gastric biopsy specimens, monoclonal PCR products were cloned and multiple clones (43 to 105) were sequenced per patient. RESULTS: Mutations were detected in all lymphoma VH sequences, which suggested germinal center or postgerminal center origin of the lymphoma B cells. In five of the eight patients, clonal heterogeneity was observed at diagnosis or during follow-up. Genealogical analysis of shared and unshared mutations showed that the process of somatic mutations was ongoing after H pylori eradication in four of the five patients who showed clonal instability. Ongoing mutations were observed in three of the four patients who completely responded to H pylori eradication, but in only one of the four patients who did not respond or who partially responded. CONCLUSION: In low-grade gastric MALT lymphomas, an ongoing process of somatic hypermutation and antigen selection can be detected after the therapeutic removal of the underlying stimulus H pylori. These data point to the relevance of yet unknown antigens that drive this disease. In addition, they challenge the view that these lymphomas may be cured solely by the eradication of H pylori.


Asunto(s)
Genes de Inmunoglobulinas/genética , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Linfoma de Células B de la Zona Marginal/genética , Mutación , Neoplasias Gástricas/genética , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Mucosa Gástrica/microbiología , Alemania , Humanos , Linfoma de Células B de la Zona Marginal/complicaciones , Linfoma de Células B de la Zona Marginal/inmunología , Masculino , Datos de Secuencia Molecular , Nueva Gales del Sur , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/inmunología
19.
J Clin Oncol ; 21(14): 2747-53, 2003 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-12860954

RESUMEN

PURPOSE: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.


Asunto(s)
Busulfano/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Linfocítica Crónica de Células B/terapia , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto , Anciano , Niño , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Probabilidad , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento
20.
Bone Marrow Transplant ; 36(12): 1083-8, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16247435

RESUMEN

A total of 22 patients with acute myeloid leukemia (AML) in first complete remission receiving autologous blood stem cell transplantation (ABSCT) were investigated in order to determine factors affecting outcome. All but two patients had a normal karyotype and received the same high-dose chemotherapy followed by G-CSF-mobilized peripheral blood stem cells after the second (n=5) or third (n=17) course of induction and post-remission chemotherapy, respectively. With a median follow-up of 30 months, the median disease-free survival is 24.1 months. Univariate analysis showed that three chemotherapy cycles before ABSCT were associated with a significant better disease-free survival (P=0.0018) and overall survival (P=0.0033), whereas the presence of an FLT3-mutation (n=6) showed no impact. The number of megakaryocytic progenitors (CFU-MK) infused tended to correlate with primary platelet engraftment (P=0.07) and were predictive for neutrophil (P=0.011) and platelet counts (P=0.009) 180 days after transplantation. Patients receiving a higher amount of CFU-MK had a better event-free survival (P=0.02). Our data suggest that the content of CFU-MK within the graft predicts the quality of hematological recovery and long-term disease control. Additionally, a minimum of three chemotherapy cycles before ABSCT seems to be associated with an improved outcome.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/citología , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Antígenos CD34/biosíntesis , Antineoplásicos/farmacología , Plaquetas , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Cariotipificación , Leucaféresis , Masculino , Megacariocitos/citología , Persona de Mediana Edad , Mutación , Inducción de Remisión , Células Madre/citología , Factores de Tiempo , Trasplante Autólogo/métodos , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA