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1.
Haematologica ; 2024 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-39113672

RESUMEN

Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.

2.
Haematologica ; 2023 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-37941409

RESUMEN

The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma (MM) is controversial. Between 2008 and 2014 a total of 217 MM patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multi-center clinical trial to compare alloTSCT to auto tandem transplantation TSCT (autoTSCT) followed by a 2-year maintenance therapy with thalidomide (100 mg/d) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent second SCT (allo n = 132 and auto n = 46). PFS at 4 years after the second SCT was 47% (CI: 38-55%) for alloTSCT and 35% (CI: 21-49%) for autoTSCT (p = 0.26). This difference increased to 22% at 8 years (p = 0.10). The cumulative incidences of non-relapse mortality (NRM) and of relapse at 4 years were 13% (CI: 8-20%) and 2% (CI: 0.3-2%) (p = 0.044) and 40% (CI: 33-50%) and 63% (CI: 50-79%) for alloTSCT and autoTSCT (p = 0.04), respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (p = 0.002). Four-year OS was 66% (CI: 57-73%) for alloTSCT and 66% (CI: 50-78%) for auto TSCT (p = 0.91) and 8-year OS was 52% and 50% (p = 0.87), respectively. AlloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly.

3.
Ann Hematol ; 102(3): 547-561, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36695874

RESUMEN

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.


Asunto(s)
Leucemia Mieloide Aguda , Mitoxantrona , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Leucemia Mieloide Aguda/tratamiento farmacológico , Mitoxantrona/efectos adversos , Pronóstico , Inducción de Remisión
4.
Blood ; 134(19): 1608-1618, 2019 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-31554635

RESUMEN

We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1+ AML, using a qRT-PC-based assay with a sensitivity of up to 10-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels (TLs) and achievement of MRD negativity (MRD-) for impact on prognosis. Achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P = .034 and P = .028, respectively). After completion of therapy, achievement of MRD- in both BM and PB was an independent, favorable prognostic factor in cumulative incidence of relapse (4-year cumulative incidence relapse: BM, 17% vs 36%, P = .021; PB, 23% vs 55%, P = .001) and overall survival (4-year overall survival rate BM, 93% vs 70%, P = .007; PB, 87% vs 47%, P < .0001). Finally, during follow-up, serial qRT-PCR analyses allowed prediction of relapse in 77% of patients exceeding a cutoff value of 150 RUNX1-RUNX1T1 TLs in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 TLs in PB. The KIT mutation was a significant factor predicting a lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TLs during treatment. Virtually all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data, we propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1+ AML.


Asunto(s)
Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Proteínas de Fusión Oncogénica/análisis , Adolescente , Adulto , Anciano , Subunidad alfa 2 del Factor de Unión al Sitio Principal/análisis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual/genética , Proteínas de Fusión Oncogénica/genética , Pronóstico , Proteína 1 Compañera de Translocación de RUNX1/análisis , Proteína 1 Compañera de Translocación de RUNX1/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Translocación Genética , Adulto Joven
5.
Ann Hematol ; 100(9): 2387-2398, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34232360

RESUMEN

Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Alemania/epidemiología , Humanos , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven
6.
Biol Blood Marrow Transplant ; 24(11): 2224-2232, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30009981

RESUMEN

Busulfan/fludarabine (BuFlu) is a widely used conditioning regimen for patients with myeloid malignancies. The sequential FLAMSA (fludarabine + Ara-C + amsacrine chemotherapy) protocol followed by either cyclophosphamide and total body irradiation (FLAMSA-TBI) or cyclophosphamide and busulfan (FLAMSA-Bu) has shown remarkable activity in high-risk acute myelogenous leukemia (AML) patients. Here we compare the outcomes of AML patients transplanted in first complete remission (CR1) or second complete remission (CR2) after conditioning with BuFlu or FLAMSA. Eligible patients had their first allogeneic stem cell transplantation for AML in CR1 or CR2 between January 2005 and June 2016. Donors were matched related or unrelated with up to 1 mismatch. Conditioning consisted of either BuFlu or FLAMSA. Propensity score matching was applied and comparisons were performed using weighted Cox regression. BuFlu conditioning was used in 1197 patients, whereas FLAMSA-TBI and FLAMSA-Bu were used in 258 and 141 patients, respectively. Median follow-up of survivors was 24.72 months. In univariate analysis, relapse incidence (RI) was 30.3%, 21.9%, and 23.1% in the BuFlu, FLAMSA-TBI, and FLAMSA-Bu groups, respectively (P < .01), and nonrelapse mortality at 2 years was 16.1%, 16.4%, and 26.7%, respectively (P < .01). Leukemia-free survival (LFS) at 2 years was 53.6%, 61.6%, and 50.1%, respectively (P = .03). Weighted Cox regression revealed that FLAMSA-TBI compared with BuFlu was associated with lower RI (hazard ratio [HR], .64; 95% confidence interval [CI], .42 to .98; P = .04) and a trend for better LFS (HR, .72; 95% CI, .49 to 1.06; P = .09). These results suggest that compared with BuFlu, conditioning with FLAMSA-TBI leads to reduced RI at 2 years in AML patients transplanted in CR1 or CR2.


Asunto(s)
Busulfano/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inducción de Remisión/métodos , Vidarabina/análogos & derivados , Busulfano/farmacología , Europa (Continente) , Femenino , Humanos , Incidencia , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Vidarabina/farmacología , Vidarabina/uso terapéutico
8.
Ann Hematol ; 94(2): 283-7, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25138222

RESUMEN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematodermic neoplasm which typically presents with skin infiltrates with or without lymphadenopathy and bone marrow involvement. No standard of care exists for this aggressive disease and prognosis is particularly poor. Here, we present our experience with nine BPDCN patients diagnosed at our institution between 2005 and 2012. BPDCN patients were identified in the databases at the Department of Hematology and Oncology, the Department of Dermatology, and the Institute of Pathology at the Otto-von-Guericke-University Magdeburg. There were six male and three female patients with a median age at diagnosis of 66 years. Sites involved were skin (five cases), lymph nodes (five cases), and bone marrow (five cases). Treatments varied from single agent chemotherapy to polychemotherapy and allogeneic stem cell transplantation for consolidation. The three patients that were treated with acute leukemia-type induction therapy followed by allogeneic stem cell transplantation (one after standard conditioning and two after reduced intensity conditioning using fludarabine in combination with thiotepa) achieved sustained remissions and are alive with a follow-up of 8, 35, and 41 months. In contrast, median survival in the less intensively treated patients was only 9.5 (range 1 to 29) months.


Asunto(s)
Células Dendríticas/patología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Neoplasias Cutáneas/terapia , Donante no Emparentado , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/métodos , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven
9.
Leukemia ; 37(2): 465-472, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36550212

RESUMEN

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20-73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Adulto , Anciano , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedad Aguda , Células Dendríticas/patología , Trastornos Mieloproliferativos/patología , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Acondicionamiento Pretrasplante , Resultado del Tratamiento
10.
J Hepatol ; 55(1): 19-28, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21145870

RESUMEN

BACKGROUND & AIMS: In this study, adenoviral vectors encoding an antisense RNA complementary to the 5' non-coding region (5'NCR) of the HCV-genome were generated to inhibit HCV-RNA gene expression in cell culture and in vivo. METHODS: First and second-generation (with E4-deletion) adenoviruses encoding the HCV5'NCR in antisense direction (Ad-NCRas and Ad-E4del-NCRas) were generated. Inhibition of HCV gene expression was analyzed in hepatoma cells stably transfected with the HCV5'NCR cDNA fused to the firefly luciferase gene (NCRluc), as well as in the HCV subgenomic replicon (genotypes 1b and 2a) and the fully infectious HCV JFH-1 cell culture systems. For in vivo experiments, an adenovirus encoding the NCRluc-gene was injected intravenously to achieve a NCR-dependent luciferase-expression in the liver of C3H/HeNcrl-mice. RESULTS: Forty eight hours after transduction with GFP-encoding adenoviruses, >85% of HepG2-, CCL13-and Huh7-cells expressed GFP. Surprisingly, GFP-expression of E4-deleted adenoviruses was considerably reduced at the same MOI. Using antisense first-generation adenoviruses (Ad-NCRas), a significant inhibition of the 5'NCR-dependent HCV-gene expression (54±19% in HepG2-cells and 66.2±15% in Huh7-cells) was achieved 48h after transduction. In Huh7-cells containing the HCV subgenomic replicons and in infectious HCV JFH-1 cell cultures, adenovirus-mediated transcription of antisense 5'NCR significantly blocked HCV-replication (40% and 76%, respectively). Corresponding to low transgene expression, the maximal inhibition reached with Ad-delE4-NCRas was 30%. In vivo, antisense adenoviral vectors also showed a significant inhibition (40%) of NCR-dependent luciferase expression compared to control adenoviruses (p<0.05). CONCLUSIONS: The data indicate that HCV gene expression can be inhibited by antisense RNA encoding adenoviruses in the tested settings.


Asunto(s)
Vectores Genéticos , Hepacivirus/genética , ARN sin Sentido/genética , Regiones no Traducidas 5' , Adenoviridae/genética , Animales , Línea Celular , Expresión Génica , Genes Virales , Hepacivirus/fisiología , Hepatitis C Crónica/terapia , Hepatitis C Crónica/virología , Técnicas In Vitro , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos C3H , Replicón , Transducción Genética , Replicación Viral/genética
11.
Leuk Lymphoma ; 62(2): 399-409, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33040622

RESUMEN

The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Anciano , Busulfano , Humanos , Leucemia Mieloide Aguda/terapia , Persona de Mediana Edad , Estudios Retrospectivos , Acondicionamiento Pretrasplante
12.
Bone Marrow Transplant ; 55(4): 729-739, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31645668

RESUMEN

Nonmyeloablative (NMA) conditioning regimens facilitate allogeneic stem cell transplantation (alloSCT) in elderly patients and/or in those with comorbidities. The acute leukemia working party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) compared the outcomes of patients ≥60 years with AML in first complete remission (CR1), that had received an alloSCT following NMA conditioning, i.e. either fludarabine/busulfan (FB2) or fludarabine/total-body-irradiation-2Gy (FluTBI2Gy). A total of 1088 patients were included (median age 65 years). Donors were matched siblings (MSD) and matched unrelated donors (MUD) in 47% and 53%, respectively. In vivo T-cell depletion (TCD) was applied to 79% and none (0%) of patients in the FB2 and FluTBI2Gy groups, respectively. In the MSD group we found a trend for less extensive cGVHD in patients receiving FB2 with in vivo TCD, HR: 0.49, p = 0.08, and in those without worse NRM, HR: 2.14, p = 0.04, and a trend for more total cGVHD, HR: 1.61, p = 0.09. Patients transplanted from MUDs had a significantly higher incidence of total cGVHD, extensive cGVHD and a worse GRFS with FluTBI2Gy in comparison to FB2, HR: 2.44; p < 0.0001; HR 4.59; p < 0.00001 and HR: 1.35; p = 0.03, respectively. No differences were observed with respect to LFS, OS, RI, NRM, and aGVHD.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Anciano , Busulfano , Humanos , Leucemia Mieloide Aguda/terapia , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Vidarabina/análogos & derivados
13.
Bone Marrow Transplant ; 54(10): 1662-1667, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30833743

RESUMEN

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for many malignant high-risk hematological diseases. The Graft-vs.-Tumor (GvT) effect is the major hallmark of this treatment approach. However, disease relapse remains a major limitation. Boosting the GvT effect by checkpoint inhibitors (CI) is an attractive option in this desperate situation although potentially triggering Graft-vs.-Host Disease (GvHD). Early reports in patients with Hodgkin's lymphoma support the idea that CI therapy after HSCT is feasible and effective. We have retrospectively analyzed CI therapy for treatment of disease recurrence after allo-HSCT other than Hodgkin's lymphoma including 21 patients from eight German transplant centers. The median follow-up was 59 days. The overall response rate (ORR) was 43%. Patients receiving donor lymphocyte infusion (DLI) in combination with CI had superior response (ORR 80%). Severe acute GvHD grade III-IV and moderate to severe chronic GvHD were observed in 29% of all patients. Taken together, CI therapy in relapsed patients after HSCT, especially in combination with DLI, is effective but induces severe GvHD in a considerable proportion of patients. Thus, prospective trials or EBMT registry-based validation of different dosing and application schedules including immunosuppressive regimens in those patients are urgently needed.


Asunto(s)
Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
15.
Leukemia ; 32(7): 1621-1630, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29720733

RESUMEN

In this phase Ib/IIa study (ClinicalTrials.gov Identifier: NCT00850382) of the German-Austrian AML Study Group (AMLSG) the multikinase inhibitor dasatinib was added to intensive induction and consolidation chemotherapy and administered as single agent for 1-year maintenance in first-line treatment of adult patients with core-binding factor (CBF) acute myeloid leukemia (AML). The primary combined end point in this study was safety and feasibility, and included the rates of early (ED) and hypoplastic (HD) deaths, pleural/pericardial effusion 3°/4° and liver toxicity 3°/4°, and the rate of refractory disease. Secondary end points were cumulative incidence of relapse (CIR) and death in complete remission (CID), and overall survival (OS). Eighty-nine pts [median age 49.5 years, range: 19-73 years; t(8;21), n = 37; inv (16), n = 52] were included. No unexpected excess in toxicity was observed. The rates of ED/HD and CR/CRi were 4.5% (4/89) and 94% (84/89), respectively. The 4-year estimated CIR, CID, and OS were 33.1% [95%-CI (confidence interval), 22.7-43.4%], 6.0% (95% CI, 0.9-11.2%), and 74.7% (95% CI, 66.1-84.5%), respectively. On the basis of the acceptable toxicity profile and favorable outcome in the AMLSG 11-08 trial, a confirmatory randomized phase III trial with dasatinib in adults with CBF-AML is ongoing (ClinicalTrials.gov Identifier: NCT02013648).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Factores de Unión al Sitio Principal/metabolismo , Dasatinib/administración & dosificación , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Recurrencia , Inducción de Remisión , Resultado del Tratamiento , Adulto Joven
16.
Clin Cancer Res ; 12(6): 1743-9, 2006 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-16551858

RESUMEN

Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Both PDGFRalpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.


Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mutación/efectos de los fármacos , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/uso terapéutico , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Benzamidas , Análisis Mutacional de ADN , Femenino , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Inhibidores de Proteínas Quinasas/uso terapéutico , Homología de Secuencia de Aminoácido
17.
Hum Gene Ther ; 14(5): 483-94, 2003 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-12691613

RESUMEN

Therapeutic vaccination with dendritic cells (DC) can lead to tumor regression in animal models and has shown promising results in the first clinical trials of metastatic renal cell carcinoma and malignant melanoma. In vitro data and results of a clinical phase I/II trial using DC tumor fusions in patients with progressive metastatic renal cell carcinoma are presented here. In addition to toxicity and feasibility, complex immune monitoring was a point of interest. DC precursor cells were obtained from the peripheral blood mononuclear cells (PBMCs) of healthy donors and were fused with either allogeneic (8 patients) or autologous (4 patients) renal tumor cells. In total, 12 patients with progressive metastatic renal cell carcinoma were treated with an average of 2.8 x 10(7) tumor cells fused with 1.8 x 10(7) DC each administered on days 0, 28, and 56 intradermally. Fusion efficacy for the tumor cells used was 14.3% +/- 7.8%. Cell viability was 59.8% +/- 6.8% after fusion and irradiation. We observed no adverse effects and no difference in clinical outcome between the allogeneic and the autologous treatment. Eight patients remained in a progressive disease state and four patients in a stable disease state. T-cell immunity was carefully monitored before, during, and after treatment. Delayed-type hypersensitivity (DTH) reaction using tumor cells was positive after treatment in 7 of 12 patients, 2 of whom were found to have stable disease. An increase in the reactivity against recall antigens was seen in most patients. Interestingly, cytotoxicity of peripheral blood lymphocytes (PBLs) against renal cell carcinoma cells increased during treatment as well as the percentage of interferon-gamma-secreting cells. This effect was significantly enhanced within the group that had stable disease. The lack of adverse effects together with positive immunologic signs justifies further investigation of this novel therapeutic approach. Further studies are necessary to test for clinical effectiveness in patients with tumors, especially those with less advanced disease.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Células Renales/terapia , Células Dendríticas/inmunología , Neoplasias Renales/terapia , Adulto , Anciano , Antígenos CD/metabolismo , Vacunas contra el Cáncer/inmunología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Fusión Celular , Citocinas/biosíntesis , Citocinas/sangre , Pruebas Inmunológicas de Citotoxicidad , Células Dendríticas/citología , Técnica del Anticuerpo Fluorescente , Humanos , Isoantígenos/inmunología , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Activación de Linfocitos , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Metástasis de la Neoplasia , Linfocitos T Citotóxicos/inmunología , Resultado del Tratamiento , Células Tumorales Cultivadas
18.
Gastroenterology ; 129(3): 1042-6, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16143141

RESUMEN

Gastrointestinal stromal tumors (GISTs) are often associated with activating KIT mutations, affecting regulatory domains of the KIT tyrosine kinase. Sporadic mastocytosis in adults is usually also caused by KIT mutations that, however, activate KIT by affecting the intracellular enzymatic site of the molecule. Most GISTs respond to KIT inhibitors that bind to the enzymatic site; in most cases of mastocytosis, however, the modified enzymatic site is not affected by these drugs. We present a kindred with both familial GISTs and mastocytosis that express a novel germline KIT mutation in exon 8, resulting in deletion of codon 419 and affecting the extracellular domain of KIT. This mutation activates KIT, and the mutant KIT is inhibited by the tyrosine kinase inhibitor imatinib mesylate. Our studies identify a new regulatory region in the KIT molecule and strongly suggest that patients with extracellular KIT mutations respond to tyrosine kinase inhibitors.


Asunto(s)
Tumores del Estroma Gastrointestinal/genética , Mutación de Línea Germinal , Mastocitosis/genética , Proteínas Proto-Oncogénicas c-kit/genética , Adulto , Niño , Femenino , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Eliminación de Secuencia
19.
Int J Cancer ; 106(6): 887-95, 2003 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-12918066

RESUMEN

Gastrointestinal stromal tumors (GISTs) typically express high levels of the Kit-receptor. The majority of GISTs carry mutations in the c-kit protooncogene clustering in exon 11. The significance of c-kit mutations for the biological behavior of GISTs is still under discussion. We evaluated 55 sporadic GISTs with available follow-up data for c-kit mutations in the juxtamembrane domain and detected mutations in 35 cases (63.6%). We found a mutational hotspot in codons 557 (tryptophan) and 558 (lysine) preferentially in histomorphologically malignant tumors. In the group of GISTs carrying c-kit mutations, 16 of 21 malignant, but only 3 of 8 benign GISTs and 3 of 6 lesions with uncertain malignant potential, carried mutations of Trp-557 and/or Lys-558. We investigated whether mutations in these 2 amino acids had an impact on biological behavior. Trp-557 and/or Lys-558 were mutated in all 15 metastatic GISTs carrying c-kit mutations but only in a minority of nonmetastatic tumors. A combined deletion of Trp-557 and Lys-558 occurred exclusively in 8 metastatic GISTs. We conclude that in addition to histomorphological evaluation determination of mutations in exon 11 may be an additional parameter for predicting the metastatic risk of GISTs and may be important for the decision that patients will need close clinical follow-up or further adjuvant treatment with kit antagonists.


Asunto(s)
Carcinoma/genética , Neoplasias Gastrointestinales/genética , Mutación/genética , Neoplasias Glandulares y Epiteliales/genética , Proteínas Proto-Oncogénicas c-kit/genética , Eliminación de Secuencia , Células del Estroma/patología , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Carcinoma/secundario , Análisis Mutacional de ADN , ADN de Neoplasias , Exones/genética , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/patología , Humanos , Lisina/genética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neoplasias Glandulares y Epiteliales/secundario , Pronóstico , Homología de Secuencia de Aminoácido , Tasa de Supervivencia , Triptófano/genética
20.
J Hepatol ; 40(5): 787-91, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15094226

RESUMEN

BACKGROUND/AIMS: In this study we established an orthotopic tumour model for hepatocellular carcinoma and evaluated a non-invasive high resolution ultrasound technique for diagnosis and follow-up of intrahepatic HCC. METHODS: Orthotopic liver tumours were induced by intrahepatic tumour cell injection of 10(5) Hepa129 hepatoma cells. Tumour establishment and growth were assessed by explorative laparotomy, ultrasound technique and hepatectomy one and two weeks after tumour cell implantation. Tumour establishment was confirmed histologically in liver sections. RESULTS: Our results show that the Hepa129 hepatoma cell line is suitable for orthotopic tumour establishment and that tumours can be diagnosed correctly by ultrasound imaging in all cases as confirmed by explorative laparotomy, hepatectomy and cross-sections. Tumour diameters obtained by explorative laparotomy correlated significantly with diameters assessed by ultrasound (r=0.7; P<0.0001). Tumour burden was slightly overestimated (1.2-fold) by ultrasound one week after tumour induction and relative tumour extensions increased 1.7-fold and 1.8-fold within one week as determined by subsequent explorative laparotomy or ultrasound imaging, respectively. CONCLUSIONS: These data demonstrate in a systematic study that ultrasound imaging can be used as a reliable tool to detect and to follow up orthotopic liver tumours in this tumour model in mice.


Asunto(s)
Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Neoplasias Hepáticas Experimentales/patología , Ratones , Ratones Endogámicos C3H , Trasplante de Neoplasias , Factores de Tiempo , Ultrasonografía/métodos
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