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1.
Klin Padiatr ; 225 Suppl 1: S79-86, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23700063

RESUMEN

The first multicenter treatment study for AML in childhood in Germany was performed from 1978 onwards. The therapy plan was designed similar to that for the acute lymphoblastic leukaemia (ALL). The drugs with the highest efficacy in AML, cytarabine cutting catara-bine and anthracyclines, were combined during induction and consolidation, followed by preventive cranial irradiation and maintenance therapy similar to that in ALL. The remission rate of the initial study was 80%, and the 5-year survival rate increased from less than 10% before 1970 to 40%. 5 subsequent trials have further increased the 5-year survival to now 70% and even 90% in the subgroup of core-binding factor leukaemias by using an intensified and optimised treatment schedule.The AML-BFM studies were the only prospective study sequence testing the benefit of cranial irradiation. Results from study -87 including the non-randomized patients showed an increased risk of CNS and/or bone marrow relapses in non-irradiated patients. Later on there was evidence that 12 Gy resulted in the same relapse rate as 18 Gy. The AML-BFM studies always used the experience from the previous study to optimize the next study. This approach was essential together with improved supportive treatment and experience of the medical staff for the step-wise and considerable increase of longterm survival within the 6 subsequent AML-BFM studies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Irradiación Craneana , Leucemia Mieloide Aguda/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Terapia Combinada , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Citarabina/efectos adversos , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Daunorrubicina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Etopósido/efectos adversos , Etopósido/uso terapéutico , Alemania , Humanos , Idarrubicina/efectos adversos , Idarrubicina/uso terapéutico , Leucemia Eritroblástica Aguda/mortalidad , Leucemia Eritroblástica Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Leucemia Promielocítica Aguda/mortalidad , Leucemia Promielocítica Aguda/terapia , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Estudios Multicéntricos como Asunto , Prednisona/efectos adversos , Prednisona/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Tioguanina/efectos adversos , Tioguanina/uso terapéutico , Vincristina/efectos adversos , Vincristina/uso terapéutico
3.
Leukemia ; 19(1): 49-56, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15538405

RESUMEN

Assessment of minimal residual disease (MRD) by flow cytometry is considered to be based on the reproducibility of the leukemic immunophenotype detected at diagnosis. However, we previously noticed modulation of surface antigen expression in acute lymphoblastic leukemia (ALL) during the early treatment. Hence, we investigated this in 30 children with B-cell precursor ALL consecutively enrolled in the AIEOP-BFM ALL 2000 protocol. Quantitative expression of seven antigens useful in MRD monitoring was studied at diagnosis and compared to that measured at different time points of remission induction therapy. Downmodulation in the expression of CD10 and CD34 occurred at follow-up. By contrast, upmodulation of CD19, CD20, CD45RA, and CD11a was observed, while the expression of CD58 remained stable. Despite this, we could unambiguously discriminate leukemic cells from normal residual B cells. This holds true when bone marrow (BM) samples from similarly treated T-ALL patients, but not from healthy donors, were used as reference. Our results indicate that immunophenotypic modulation occurs in ALL during the early phases of BFM-type protocols. However, the accuracy of MRD detection by flow cytometry seems not negatively affected if adequate analysis protocols are employed. Investigators should take this phenomenon into account in order to avoid pitfalls in flow cytometric MRD studies.


Asunto(s)
Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Antígenos CD/inmunología , Niño , Estudios de Cohortes , Humanos , Inmunofenotipificación , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inducción de Remisión
4.
Leukemia ; 17(6): 1121-3, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12764378

RESUMEN

Recurrent chromosomal abnormalities present in malignant cells often define subentities with unique biological and clinical features. The molecular identification of genes involved in genetic alterations has led to the characterization of fusion genes with neoplastic properties. However, for many nonrandom translocations including the dic(9;12)(p11-13;p11-12), the molecular equivalent has not as yet been identified. The dicentric translocation dic(9;12) is a recurrent chromosome abnormality that accounts for close to 1% of childhood acute lymphoblastic leukemia (ALL). This specific alteration occurs almost exclusively in B-progenitor ALL, and unlike many other nonrandom translocations, is associated with an excellent prognosis. In this work, we provide strong evidence that the PAX5/ETV6 fusion transcript defines the clinical and biological entity that is associated with the presence of a dic(9;12) chromosome. As the PAX5 and ETV6 genes are localized at 9p13 and 12p13, respectively, the cytogenetic description of the dic(9;12)-PAX5/ETV6 rearrangement should be refined to dic(9;12)(p13;p13).


Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 9 , Proteínas de Unión al ADN/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Translocación Genética , Adolescente , Antígenos CD/metabolismo , Fusión Artificial Génica , Linfocitos B/patología , Linfoma de Burkitt/genética , Niño , Aberraciones Cromosómicas , Cartilla de ADN/química , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Factor de Transcripción PAX5 , Proteínas Proto-Oncogénicas c-ets , ARN Neoplásico/sangre , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína ETS de Variante de Translocación 6
5.
Leukemia ; 11(8): 1266-73, 1997 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9264380

RESUMEN

We studied the differentiation profiles of B cell precursors (BCP) in normal and post-chemotherapy pediatric bone marrow (BM) using multiparameter flow cytometry. The goal of our study was to draw a comprehensive phenotypic map of the three major maturational BCP stages in BM. By correlating lineage-associated markers, CD45RA, and several adhesion molecules, the stage-specific patterns were found to differ in certain details from previously published concepts. Among the earliest BCP, a subset of CD34+ CD10(lo) precursors was repeatedly observed in addition to the well characterized CD34+ CD10(hi) CD19+ majority of cells. Only two-thirds of these CD34+ CD10(lo) cells expressed CD19. However, uniformity of phenotypic features, absence of T lineage markers, and the regeneration kinetics after chemotherapy suggest the B lineage affiliation of the CD34+ CD10(lo) precursors in general. In the more mature BCP, expression of CD10, CD20, cytoplasmic and surface mu chains (c mu and s mu) was observed to overlap more than previously recognized. We found that CD20 and c mu appear early during B cell ontogeny (already on CD34+ BCP), and that CD10 is lost late, following the onset of s mu expression. Differences between normal and post-chemotherapy BM specimens regarding the phenotypic appearance of BCP were exclusively due to differences in the subset composition, as post-chemotherapy samples showed a preponderance of immature stages. Our observations may build a framework for comparing leukemic cells with their normal counterparts to define possible leukemia-associated aberrations useful for residual disease studies.


Asunto(s)
Linfocitos B/citología , Células de la Médula Ósea , Hematopoyesis , Adolescente , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos B/análisis , Antineoplásicos/farmacología , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular , Niño , Preescolar , Citometría de Flujo , Hematopoyesis/efectos de los fármacos , Humanos , Cadenas mu de Inmunoglobulina/metabolismo , Inmunofenotipificación , Leucemia/tratamiento farmacológico , Leucemia/patología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , Receptores de Antígenos de Linfocitos B/metabolismo
6.
Leukemia ; 18(10): 1611-6, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15356655

RESUMEN

The aim of the present study was to determine the frequency and clinical relevance of the most common secondary karyotype abnormalities in TEL/AML1+ B-cell precursor acute lymphoblastic leukemia (ALL) as assessed with fluorescence in situ hybridization (FISH) analyses. Screening of 372 patients who were enrolled in two consecutive Austrian childhood ALL multicenter trials identified 94 (25%) TEL/AML1+ cases. TEL deletions, trisomy 21 and an additional der(21)t(12;21) were detected in 52 (55%), 13 (14%) and 14 (15%) TEL/AML1+ patients, respectively. The 12p aberrations (P=0.001) and near tetraploidy (P=0.045) were more common in TEL/AML1+ patients, whereas the incidence of diploidy, pseudodiploidy, hypodiploidy, low hyperdiploidy, near triploidy, del(6q), chromosome 9 and 11q23 abnormalities was similar among TEL/AML1+ and TEL/AML1- patients. None of the TEL/AML1+ patients had a high hyperdiploid karyotype. Univariate analysis indicated that among TEL/AML1+ patients those with a deletion of the nontranslocated TEL allele had a worse prognosis than those without this abnormality (P=0.034). We concluded that the type and incidence of the most common secondary aberrations in TEL/AML1+ ALL can be conveniently identified with little additional effort during interphase screening with appropriate TEL and AML1 FISH probes. We also provided preliminary evidence that the deletion of the nontranslocated TEL allele may adversely influence the clinical course of TEL/AML1+ ALL.


Asunto(s)
Aberraciones Cromosómicas , Interfase/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Niño , Preescolar , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 21/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Síndrome de Down , Femenino , Eliminación de Gen , Humanos , Hibridación Fluorescente in Situ , Incidencia , Lactante , Cariotipificación , Masculino , Proteínas de Fusión Oncogénica/genética , Ploidias , Estudios Retrospectivos , Translocación Genética
7.
Leukemia ; 18(4): 703-8, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-14961034

RESUMEN

Expression of CD99 is higher on immature than on mature T cells. We postulated that this marker could be used to assess minimal residual disease (MRD) in T-lineage acute lymphoblastic leukemia (T-ALL). In diagnostic bone marrow (BM) samples from 27 children with T-ALL, expression of CD99 on leukemic lymphoblasts by flow cytometry was in median 7.7 times higher than on normal T lymphocytes from within the same sample. In 85% of cases, leukemic MFI values were higher than the mean MFI+2 s.d. of normal populations. We applied CD99 to study MRD in 39 follow-up samples from 15 consecutive T-ALL patients, and compared the results with those obtained with the well-established MRD-marker terminal deoxynucleotidyl transferase (TdT). Either antibody was combined in four-color flow cytometry with CD7, surfaceCD3, and cytoplasmicCD3. We found that CD99 was a valid complement to TdT in quantifying T-ALL MRD. Given a considerable interpatient variability, CD99 could be favorably used in nine patients, and TdT in other five patients. Both approaches showed a similar very low nonspecific background throughout 12 weeks from diagnosis (in median 0.002% of nucleated BM cells in patients with non-T ALL). We conclude that CD99 is a highly informative tool for MRD detection in T-ALL, bearing the advantage of surface expression in contrast to TdT.


Asunto(s)
Antígenos CD/análisis , Moléculas de Adhesión Celular/análisis , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Antígeno 12E7 , Adolescente , Biomarcadores de Tumor/análisis , Examen de la Médula Ósea , Niño , Preescolar , ADN Nucleotidilexotransferasa/análisis , Femenino , Citometría de Flujo , Humanos , Lactante , Masculino , Técnicas de Diagnóstico Molecular , Sensibilidad y Especificidad , Linfocitos T/inmunología , Linfocitos T/patología
8.
Exp Hematol ; 26(4): 305-13, 1998 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9546313

RESUMEN

Leukemic cells of B-lineage acute lymphoblastic leukemia (ALL) are regarded as the malignant counterparts of immature, physiologic B cell precursors (BCPs). To determine whether phenotypic differences exist between these corresponding cell types, we investigated samples of normal pediatric bone marrow (n=30) as well as of B-precursor ALL at diagnosis (n=53; common and pre-B subtype). Using three-color multiparameter flow cytometric analysis, we compared the leukemic populations with the physiologic BCPs of corresponding maturity with respect to the intensity with which they expressed a series of antigens. In some of these antigens, leukemia-associated aberrations were frequently observed. In particular, overexpression of CD10 was displayed by 65% of ALL samples, whereas 58% of leukemic cases aberrantly exhibited very low or no CD45RA expression. Regarding CD11a and CD44, 47% and 35% of ALL populations were aberrant as defined by either the absence or significant overexpression of the antigen. In contrast, antigen densities of CD49d, CD49e, and CD99 on leukemic cells were in the normal range of values for BCPs. Combining the patterns of frequently aberrant markers in a comprehensive analysis, we were able to identify individual phenotypic leukemic cell aberrations in up to 98% of investigated cases. CD10 and/or CD45RA were aberrant in 86% of cases overall, emphasizing the high discriminative potential of these two markers. Using comparative phenotype mapping based on quantitatively aberrant, leukemia-associated antigenic patterns, we were able to detect leukemic blasts among normal bone marrow cells at frequencies as low as 10(-5). We speculate that our approach may have a profound impact on the development of new strategies for minimal residual disease investigations in patients with BCP-ALL.


Asunto(s)
Linfocitos B/patología , Hematopoyesis , Inmunofenotipificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Linfocitos B/inmunología , Células de la Médula Ósea/patología , Antígenos CD11/análisis , Niño , Preescolar , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Células Madre Hematopoyéticas/patología , Humanos , Receptores de Hialuranos/análisis , Lactante , Antígenos Comunes de Leucocito/análisis , Neprilisina/análisis
9.
Exp Hematol ; 27(4): 673-81, 1999 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10210325

RESUMEN

We recently investigated samples of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and normal bone marrow (BM). We found that leukemic blasts, compared to their physiologic counterpart cells, frequently display aberrant phenotypes with respect to levels of expression of certain antigens. Using multiparameter flow cytometry, these differences enabled us to trace leukemic cells admixed to normal BM, which suggested that this approach might be a useful strategy for minimal residual disease detection. In the present study, we used the same multiparameter approach ("comparative phenotype mapping") to prove that such quantitative phenotypic differences really exist between malignant and normal BCP when simultaneously present in the BM. We demonstrate this by five exemplary follow-up BM samples from patients with BCP-ALL, all of which showed phenotypically aberrant cells according to levels of expression of CD10, CD11a, CD19, CD34, CD44, or CD45RA, as well as according to altered orthogonal light scattering properties. We confirmed the leukemic nature of these cells by polymerase chain reaction-based detection of bcr1/abl transcripts, and of leukemia clone-specific immunoglobulin heavy chain rearrangements in only the suspicious cells when sorted by flow cytometry, but not in normal BCP or non-B cells. Comparative phenotype mapping thus allows one to distinguish between normal and leukemic cells, and we show that it may enable rapid, specific, and quantitative detection of residual/resurgent leukemia in BCP-ALL.


Asunto(s)
Inmunofenotipificación , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Antígenos CD/metabolismo , Células de la Médula Ósea/metabolismo , Examen de la Médula Ósea , Niño , Preescolar , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Masculino , Fenotipo , Proyectos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Valor Predictivo de las Pruebas
10.
Leuk Lymphoma ; 38(3-4): 295-308, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10830736

RESUMEN

The present review summarizes our efforts in developing a novel immunologic approach ("Comparative Phenotype Mapping") targeted at assessing minimal residual disease (MRD) in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) patients. The method relies on quantitatively aberrant, leukemia-associated antigen expression patterns which allow to discriminate leukemic from normal BCP using a limited panel of antibody combinations and multidimensional flow cytometry. In an analysis of 63 follow up bone marrow samples of patients with BCP-ALL we show that this approach enables to efficiently detect MRD. Further clinical observation revealed that the patients which were MRD-positive by flow cytometry (although in morphological remission) had a very high probability of early disease recurrence compared to the good chances of a relapse-free survival (RFS) in the MRD-negative cohort (RFS 0.0 vs. 0.76 at 3 years). Comparative Phenotype Mapping thus proves to be a reliable method for MRD detection in BCP-ALL. Concluding remarks relate to the optional applications of the method as well as to future perspectives. An ongoing large prospective study which we are now conducting on the basis of Comparative Phenotype Mapping will clarify the clinical significance of MRD detection in ALL patients by this method, and will determine its value compared to related as well as molecular-genetic techniques.


Asunto(s)
Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Subgrupos de Linfocitos B/química , Biomarcadores de Tumor/análisis , Citometría de Flujo/métodos , Inmunofenotipificación , Células Madre Neoplásicas/química , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Subgrupos de Linfocitos B/patología , Médula Ósea/patología , Diferenciación Celular , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Predicción , Regulación Leucémica de la Expresión Génica , Humanos , Lactante , Tablas de Vida , Neoplasia Residual , Células Madre Neoplásicas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Resultado del Tratamiento
13.
Cell Death Dis ; 3: e425, 2012 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-23152061

RESUMEN

CD99 is present in many human cell types, including high-level surface expression on pediatric B and T leukemias and Ewing tumors (ETs). On B lymphocytes and respective malignancies, its level decreases with the stage of maturation. Inter-individual variability of CD99 on B-cell precursor acute lymphoblastic leukemia (BCP-ALL) blasts was shown recently to be associated with distinct cytogenetic backgrounds. However, CD99 targets remain mainly unknown. Here, we show that administration of an anti-CD99 antibody to B- and T-leukemia cell lines induces heat shock protein 70 (HSP70), both on the cell surface and in the cytoplasm. Investigation of primary BCP-ALL cells rendered similar results. Intriguingly, CD99-induced modulation of HSP70 on ET cells had profiles different from that on leukemia cells. Since HSP70 expression on tumor cells is a prerequisite for natural killer (NK) cell-mediated tumor lysis, we hypothesized that CD99-induced HSP70 may allow targeting of some CD99-positive malignancies via NK-cell cytotoxicity. Our experiments with NK92 cell line demonstrated that leukemia cells with upregulated HSP70 can be successfully killed by effector cells. We consider our data as a new view of CD99 functions and as a basis for the development of a potential anti-tumor strategy based on heat-shock protein activation via CD99 triggering.


Asunto(s)
Antígenos CD/inmunología , Moléculas de Adhesión Celular/inmunología , Proteínas HSP70 de Choque Térmico/genética , Células Asesinas Naturales/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Regulación hacia Arriba , Antígeno 12E7 , Linfocitos B/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica , Proteínas HSP70 de Choque Térmico/inmunología , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfocitos T/inmunología
14.
Leukemia ; 26(5): 927-33, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22094587

RESUMEN

The ETV6/RUNX1 (E/R) gene fusion is generated by the t(12;21) and found in approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia. In contrast to the overwhelming evidence that E/R is critical for the initiation of leukemia, its relevance for the maintenance of overt disease is less clear. To investigate this issue, we suppressed the endogenous E/R fusion protein with lentivirally transduced short hairpin RNA in the leukemia cell lines REH and AT-2, and found a distinct reduction of proliferation and cell survival. In line with the observed concurrent inactivation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, pharmacological inhibition diminished the phosphorylation of AKT and ribosomal protein S6, and significantly increased the apoptosis rate in E/R-positive leukemias. Moreover, PI3K/mTOR inhibitors sensitized glucocorticoid-resistant REH cells to prednisolone, an observation of potential relevance for improving treatment of drug-resistant relapses. Of note, knockdown of the E/R fusion gene also severely impaired the repopulation capacity of REH cells in non-obese deficient/severe combined immunodeficient mice. Collectively, these data demonstrate that the E/R fusion protein activates the PI3K/AKT/mTOR pathway and is indispensible for disease maintenance. Importantly, these results provide a first rationale and justification for targeting the fusion gene and the PI3K/AKT/mTOR pathway therapeutically.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Silenciador del Gen , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa , Trasplante Heterólogo , Proteína ETS de Variante de Translocación 6
15.
Leukemia ; 26(4): 654-61, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21968880

RESUMEN

Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n = 59) and -2004 (n = 66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66 ± 4%, and improved from 61 ± 6% in study-98 to 75 ± 6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44 ± 6% and 51 ± 6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.


Asunto(s)
Leucemia Mieloide Aguda/terapia , Antraciclinas/administración & dosificación , Niño , Preescolar , Citarabina/administración & dosificación , Femenino , Trasplante de Células Madre Hematopoyéticas , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Análisis Multivariante , Proteína de la Leucemia Mieloide-Linfoide/genética , Terapia Recuperativa , Resultado del Tratamiento
18.
Leukemia ; 23(7): 1264-9, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19212332

RESUMEN

In the management of the childhood acute lymphoblastic leukemia (ALL), 5% of failures are due to induction death and treatment-related deaths in first complete remission. We retrospectively analyzed the incidence, pattern and causes of death and its risk factors for 896 children with ALL enrolled into five Austrian (A) Berlin-Frankfurt-Münster (BFM) trials between 1981 and 1999. The estimated 10-year cumulative incidence of death significantly decreased from 6+/-1% (n=16/268) in trials ALL-BFM-A 81 and ALL-A 84 to 2+/-1% (n=15/628) in trials ALL-BFM-A 86, 90 and 95 (P=0.006). A significant reduction of death was evident during induction therapy (2.2% in trials ALL-BFM-A 81 and ALL-A 84 and 0.2% in trials ALL-BFM-A 86, 90 and 95, P=0.001). Of 31 patients, 21 (68%) patients died from infectious and 10 (32%) from noninfectious complications. Treatment in trial ALL-BFM-A 81, infant age and female gender were independent predictors of an enhanced risk for death. Conclusively, we found a progressive reduction of death rates that may be explained by the increasing experience in specialized hemato-oncologic centers and improved supportive and intensive care. We also identified a distinct subset of patients who are especially prone to death and may need a special focus when receiving intense chemotherapy.


Asunto(s)
Antineoplásicos/toxicidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inducción de Remisión , Causas de Muerte , Niño , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico
20.
Onkologie ; 24(5): 442-8, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11694770

RESUMEN

Assessment of minimal residual disease (MRD) during the first months of therapy gives information on the timely response to treatment, and proves to be a powerful and independent indicator of treatment outcome in patients with acute lymphoblastic leukemia (ALL). Immunological evaluation by flow cytometry (FC) is one of the most attractive approaches to this. The present review summarizes the historical development of the technique over the last 20 years, showing that current methodology is based on the existence of leukemia-associated patterns of asynchrony in antigen expression with respect to normal differentiation or location of occurrence. Such asynchrony allows the sensitive detection of rare malignant cells by multiparametric FC, although completely leukemia-specific antigens for broad application do not exist. Clinical studies proved that the technology should now be applicable to almost all patients with ALL and that immunological MRD results correlate well with outcome. However, based on the available set of FC data, it is yet too early to draw firm conclusions for clinical application. Issues still to be addressed by comprehensive and non-selecting investigations on the basis of the most widely used treatment protocols are whether 1) quantitative data generated by PCR and FC are interchangeable, 2) differences between therapeutic regimens influence the significance of qualitative and quantitative aspects of MRD, and 3) absolute enumeration of MRD bears advantages over the common practice of relative quantification. Concluding remarks further relate to technical issues which may allow to simplify the approach in the future which should augment also its economic efficiency.


Asunto(s)
Linfocitos B/inmunología , Epítopos de Linfocito B/sangre , Citometría de Flujo , Inmunofenotipificación , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Humanos , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/inmunología , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Valor Predictivo de las Pruebas , Pronóstico
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