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BACKGROUND: Characterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS). PATIENTS AND METHODS: Patients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial. RESULTS: Compared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P = 0.08; 11.1 ± 1% for grade 0, P = 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) = 2.1, P = 7 × 10- 8). TT-homozygotes had a 6.5-fold increased risk of hyperbilirubinemia (grades 1-4; 95% confidence interval (CI) = 2.9-14.6, P = 7 × 10- 6) and a 16.4-fold higher risk of grade 3-4 hyperbilirubinemia (95% CI 6.1-43.8, P = 2 × 10- 8). Replication analyses confirmed these associations with joint analysis yielding genome-wide significance (allelic OR = 2.1, P = 6 × 10- 11; 95% CI 1.7-2.7). Moreover, rs6744284 genotypes were strongly linked to the Gilbert's syndrome-associated UGT1A1*28/*37 allele (r2 = 0.70), providing functional support for study findings. Of clinical importance, the rs6744284 TT genotype counterbalanced the adverse prognostic impact of high hyperbilirubinemia on therapy outcome. CONCLUSIONS: Chemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov ; #NCT00430118.
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Estudio de Asociación del Genoma Completo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Bilirrubina/uso terapéutico , Hiperbilirrubinemia/inducido químicamente , Hiperbilirrubinemia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Resultado del Tratamiento , NiñoRESUMEN
Recently, we defined "CML-like" subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000-IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Proteínas de Fusión bcr-abl/genética , Neoplasia Residual/genética , Estudios Retrospectivos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Enfermedad AgudaRESUMEN
The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins, it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line "clonal origin" an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years, and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal derivation. However, older production cell lines developed before the implementation of these methods, herein referred to as "legacy cell lines," may not meet current regulatory expectations for demonstration of clonal derivation. In this article, the members of the IQ Consortium Working Group on Clonality present our position that the demonstration of process consistency and product comparability of critical quality attributes throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal derivation standards. With this commentary, we discuss advantages and limitations of genetic testing methods to support clonal derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to Investigational New Drug (IND) application and before demonstration of product and process consistency at Biologics License Applications (BLA) submission.
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Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Desarrollo de Medicamentos/métodos , Pruebas Genéticas/métodos , Secuenciación Completa del Genoma/métodos , Animales , Células CHO , Línea Celular , Cricetinae , Cricetulus , Desarrollo de Medicamentos/normas , Pruebas Genéticas/normas , Desarrollo de Programa/métodos , Desarrollo de Programa/normas , Secuenciación Completa del Genoma/normasRESUMEN
The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
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Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Glicosiltransferasas/genética , Antígenos HLA/genética , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Pronóstico , Factores de RiesgoRESUMEN
Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.
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Eliminación de Gen , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Niño , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Humanos , Masculino , Neoplasia Residual/genética , Neoplasia Residual/patología , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Receptor PAR-1/genéticaRESUMEN
Systemic amyloidosis is caused by the misfolding of a circulating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs. Chemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology, the fibril protein primary and secondary structures, the presence of post-translational modifications and, in case of the AL fibrils, the partially folded characteristics of the polypeptide chain within the fibril. Our data imply for both analyzed forms of amyloidosis that the pathways of protein misfolding are systemically conserved; that is, they follow the same rules irrespective of where inside one body fibrils are formed or accumulated.
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Precursor de Proteína beta-Amiloide/metabolismo , Amiloidosis/metabolismo , Pliegue de Proteína , Tejido Adiposo/metabolismo , Secuencia de Aminoácidos , Animales , Electroforesis en Gel de Poliacrilamida , Humanos , Espectrometría de Masas , Ratones , Microscopía Electrónica de Transmisión , Miocardio/metabolismo , Péptidos/metabolismo , Procesamiento Proteico-Postraduccional , Estructura Secundaria de Proteína , Bazo/metabolismo , Difracción de Rayos XRESUMEN
Polymorphism is a wide-spread feature of amyloid-like fibrils formed inâ vitro, but it has so far remained unclear whether the fibrils formed within a patient are also affected by this phenomenon. In this study we show that the amyloid fibrils within a diseased individual can vary considerably in their three-dimensional architecture. We demonstrate this heterogeneity with amyloid fibrils deposited within different organs, formed from sequentially non-homologous polypeptide chains and affecting human or animals. Irrespective of amyloid type or source, we found inâ vivo fibrils to be polymorphic. These data imply that the chemical principles of fibril assembly that lead to such polymorphism are fundamentally conserved inâ vivo and inâ vitro.
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Amiloide/química , Microscopía Electrónica de Transmisión , Conformación ProteicaRESUMEN
Minimal residual disease (MRD) at the end of induction therapy is important for risk stratification of acute lymphoblastic leukaemia (ALL), but bone marrow (BM) aspiration is often postponed or must be repeated to fulfil qualitative and quantitative criteria for morphological assessment of haematological remission and/or MRD analysis. The impact of BM aspiration delay on measured MRD levels and resulting risk stratification is currently unknown. We analysed paired MRD data of 289 paediatric ALL patients requiring a repeat BM aspiration. MRD levels differed in 108 patients (37%) with a decrease in the majority (85/108). This would have resulted in different risk group allocation in 64 of 289 patients (23%) when applying the ALL-Berlin-Frankfurt-Münster 2000 criteria. MRD change was associated with the duration of delay; 40% of patients with delay ≥7 days had a shift to lower MRD levels compared to only 18% after a shorter delay. Patients MRD-positive at the original but MRD-negative at the repeat BM aspiration (n = 50) had a worse 5-year event-free survival than those already negative at first aspiration (n = 115) (86 ± 5% vs. 94 ± 2%; P = 0·024). We conclude that BM aspirations should be pursued as scheduled in the protocol because delayed MRD sampling at end of induction may result in false-low MRD load and distort MRD-based risk assessment.
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Examen de la Médula Ósea/métodos , Errores Diagnósticos/prevención & control , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Biopsia con Aguja Fina , Niño , Preescolar , Diagnóstico Tardío , Femenino , Humanos , Lactante , Masculino , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Inducción de Remisión , Medición de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.
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Cromosomas Humanos Par 9/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Niño , Preescolar , Exones/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Prevalencia , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, 'type 1' relapse derives from the primary leukemia whereas 'type 2' relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition.
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Metilación de ADN , ADN de Neoplasias , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Regiones Promotoras Genéticas , Adolescente , Niño , Preescolar , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologíaRESUMEN
Acute lymphoblastic leukemia (ALL) accounts for â¼25% of pediatric malignancies. Of interest, the incidence of ALL is observed â¼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in â¼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls.
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Proteínas Portadoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recombinasas/genética , Recombinación V(D)J , Adolescente , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Niño , Preescolar , Estudios de Cohortes , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Eliminación de Gen , Humanos , Lactante , Masculino , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Proteína 1 de la Leucemia Linfocítica T Aguda , Proteína ETS de Variante de Translocación 6RESUMEN
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.
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Cromosomas Humanos Par 10 , Factor de Transcripción GATA3/genética , Fenotipo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Edad , Alelos , Linfocitos B/metabolismo , Linfocitos B/patología , Niño , Exones , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Intrones , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Análisis de SupervivenciaRESUMEN
Despite improvements in treatment results for pediatric T-cell acute lymphoblastic leukemia, approximately 20% of patients relapse with dismal prognosis. PTEN inactivation and NOTCH1 activation are known frequent leukemogenic events but their effect on outcome is still controversial. We analyzed the effect of PTEN inactivation and its interaction with NOTCH1 activation on treatment response and long-term outcome in 301 ALL-BFM treated children with T-cell acute lymphoblastic leukemia. We identified PTEN mutations in 52 of 301 (17.3%) of patients. In univariate analyses this was significantly associated with increased resistance to induction chemotherapy and a trend towards poor long-term outcome. By contrast, patients with inactivating PTEN and activating NOTCH1 mutations showed marked sensitivity to induction treatment and excellent long-term outcome, which was similar to patients with NOTCH1 mutations only, and more favorable than in patients with PTEN mutations only. Notably, in the subgroup of patients with a prednisone- and minimal residual disease (MRD)-response based medium risk profile, PTEN-mutations without co-existing NOTCH1-mutations represented an MRD-independent highly significant high-risk biomarker. Mutations of PTEN highly significantly indicate a poor prognosis in T-ALL patients who have been stratified to the medium risk group of the BFM-protocol. This effect is clinically neutralized by NOTCH1 mutations. Although these results have not yet been explained by an obvious molecular mechanism, they contribute to the development of new molecularly defined stratification algorithms. Furthermore, these data have unexpected potential implications for the development of NOTCH1 inhibitors in the treatment of T-cell acute lymphoblastic leukemia in general, and in those with a combination of PTEN and NOTCH1 mutations in particular.
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Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Niño , Preescolar , Femenino , Humanos , Masculino , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Pronóstico , Resultado del TratamientoRESUMEN
IKZF1 gene deletions have been associated with a poor outcome in pediatric precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance of IKZF1 deletions for patients treated on Berlin-Frankfurt-Münster Study Group trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia samples by Multiplex Ligation-dependent Probe Amplification. Patients whose leukemic cells bore IKZF1 deletions had a lower 5-year event-free survival (0.69±0.05 vs. 0.85±0.01; P<0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (0.21±0.04 vs. 0.10±0.01; P=0.001). Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2 rearrangement, their prognostic value was found to be independent from this association. Thus, IKZF1 deletion is an independent predictor of treatment outcome and a strong candidate marker for integration in future treatment stratification strategies on ALL-BFM protocols. Clinicaltrials.gov identifier: NCT00430118.
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Eliminación de Gen , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Numerous reports have been published on the association between kinetics of leukemic cells during early treatment of childhood acute lymphoblastic leukemia and therapeutic outcome. In contrast, little is known about the prognostic relevance of normal blood counts in this setting. DESIGN AND METHODS: Normal hematopoiesis during and after induction treatment (days 8, 15 and 33) was correlated with therapeutic outcome in a cohort of 256 children with acute lymphoblastic leukemia treated in one of three consecutive ALL-BFM trials at a single institute. Replication analysis of positive findings was performed in an independent cohort of 475 patients from the ALL-BFM 2000 multicenter trial. RESULTS: A platelet count in the first quartile on treatment day 33 and a neutrophil count above the median on day 8 were significantly associated with treatment outcome, conferring multivariate risk ratios for an event of 3.27 (95% confidence interval 1.60-6.69) and 2.26 (95% confidence interval 1.23-4.29), respectively. Replication analysis confirmed the prognostic effect of platelet count on treatment day 33 and demonstrated a strong association with minimal residual disease-based risk group distribution (P<0.00001). CONCLUSIONS: Platelet counts after induction treatment may improve treatment stratification for patients with childhood acute lymphoblastic leukemia and be of particular interest in non-minimal residual disease-based trials. (ALL-BFM 2000 is registered at: ClinicalTrials.gov: NCT00430118. National Cancer Institute: Protocol ID 68529).
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Quimioterapia de Inducción , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Recuento de Células Sanguíneas , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Neoplasia Residual , Recuento de Plaquetas , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers; MRD intermediate risk (MRD-IR) if positive either at day 33 or 78 and < 10(-3) at day 78; and MRD high risk (MRD-HR) if ≥ 10(-3) at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE) was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients). MRD ≥ 10(-3) at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials.gov; "Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia," protocol identification #NCT00430118 for BFM and #NCT00613457 for AIEOP.
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Leucemia-Linfoma Linfoblástico de Células T Precursoras/clasificación , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Reordenamiento Génico de Linfocito B , Reordenamiento Génico de Linfocito T , Humanos , Lactante , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage.
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Cromosomas Humanos Par 9 , Genes p16 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000) study has for the first time introduced standardized quantitative assessment of minimal residual disease (MRD) based on immunoglobulin and T-cell receptor gene rearrangements as polymerase chain reaction targets (PCR-MRD), at 2 time points (TPs), to stratify patients in a large prospective study. Patients with precursor B (pB) ALL (n = 3184) were considered MRD standard risk (MRD-SR) if MRD was already negative at day 33 (analyzed by 2 markers, with a sensitivity of at least 10(-4)); MRD high risk (MRD-HR) if 10(-3) or more at day 78 and MRD intermediate risk (MRD-IR): others. MRD-SR patients were 42% (1348): 5-year event-free survival (EFS, standard error) is 92.3% (0.9). Fifty-two percent (1647) were MRD-IR: EFS 77.6% (1.3). Six percent of patients (189) were MRD-HR: EFS 50.1% (4.1; P < .001). PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. MRD response detected by sensitive quantitative PCR at 2 predefined TPs is highly predictive for relapse in childhood pB-ALL. The study is registered at http://clinicaltrials.gov: NCT00430118 for BFM and NCT00613457 for AIEOP.