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BACKGROUND: There are no studies assessing the evolution and patterns of genetic studies performed at diagnosis in acute myeloid leukemia (AML) patients. Such studies could help to identify potential gaps in our present diagnostic practices, especially in the context of increasingly complex procedures and classifications. METHODS: The REALMOL study (NCT05541224) evaluated the evolution, patterns, and clinical impact of performing main genetic and molecular studies performed at diagnosis in 7285 adult AML patients included in the PETHEMA AML registry (NCT02607059) between 2000 and 2021. RESULTS: Screening rates increased for all tests across different time periods (2000-2007, 2008-2016, and 2017-2021) and was the most influential factor for NPM1, FLT3-ITD, and next-generation sequencing (NGS) determinations: NPM1 testing increased from 28.9% to 72.8% and 95.2% (p < .001), whereas FLT3-ITD testing increased from 38.1% to 74.1% and 95.9% (p < .0001). NGS testing was not performed between 2000-2007 and only reached 3.5% in 2008-2016, but significantly increased to 72% in 2017-2021 (p < .001). Treatment decision was the most influential factor to perform karyotype (odds ratio [OR], 6.057; 95% confidence interval [CI], 4.702-7.802), and fluorescence in situ hybridation (OR, 2.273; 95% CI, 1.901-2.719) studies. Patients ≥70 years old or with an Eastern Cooperative Oncology Group ≥2 were less likely to undergo these diagnostic procedures. Performing genetic studies were associated with a favorable impact on overall survival, especially in patients who received intensive chemotherapy. CONCLUSIONS: This unique study provides relevant information about the evolving landscape of genetic and molecular diagnosis for adult AML patients in real-world setting, highlighting the increased complexity of genetic diagnosis over the past 2 decades.
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The molecular landscape of acute lymphoblastic leukemia (ALL) is highly heterogeneous, and genetic lesions are clinically relevant for diagnosis, risk stratification, and treatment guidance. Next-generation sequencing (NGS) has become an essential tool for clinical laboratories, where disease-targeted panels are able to capture the most relevant alterations in a cost-effective and fast way. However, comprehensive ALL panels assessing all relevant alterations are scarce. Here, we design and validate an NGS panel including single-nucleotide variants (SNVs), insertion-deletions (indels), copy number variations (CNVs), fusions, and gene expression (ALLseq). ALLseq sequencing metrics were acceptable for clinical use and showed 100% sensitivity and specificity for virtually all types of alterations. The limit of detection was established at a 2% variant allele frequency for SNVs and indels, and at a 0.5 copy number ratio for CNVs. Overall, ALLseq is able to provide clinically relevant information to more than 83% of pediatric patients, making it an attractive tool for the molecular characterization of ALL in clinical settings.
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Variaciones en el Número de Copia de ADN , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Mutación INDEL , Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Polimorfismo de Nucleótido SimpleRESUMEN
PURPOSE OF REVIEW: The development of high-throughput techniques like next-generation sequencing (NGS) has unraveled the genetic profile of cancer. In this review, we discuss the role of NGS on the diagnostic, risk stratification, and follow-up of patients with acute myeloid leukemia (AML). RECENT FINDINGS: NGS has become an essential tool in clinical practice for AML management. Therefore, efforts are being made to improve its applications, automation, and turnaround time. Other high-throughput techniques, such as whole genome sequencing or RNA-sequencing, can be also used to this end. However, not all institutions may be able to implement these approaches. NGS is being investigated for measurable residual disease (MRD) assessment, especially with the development of error-correction NGS. New data analysis approaches like machine learning are being investigated in order to integrate genomic and clinical data and develop comprehensive classifications and risk scores. SUMMARY: NGS has proven to be a useful approach for the analysis of genomic alterations in patients with AML, which aids patient management. Current research is being directed at reducing turnaround time and simplifying processes so that these techniques can be universally integrated into clinical practice.
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Leucemia Mieloide Aguda , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , Neoplasia Residual/genética , ARNRESUMEN
BACKGROUND: Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). METHODS: Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. RESULTS: The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). CONCLUSIONS: FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.
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Citarabina , Leucemia Mieloide Aguda , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina , Humanos , Leucemia Mieloide Aguda/terapia , Inducción de Remisión , Resultado del Tratamiento , Vidarabina/análogos & derivadosRESUMEN
Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.
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Leucemia Mieloide Aguda , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , RecurrenciaRESUMEN
Prognosis for relapsed or refractory (R/R) acute myeloid leukemia (AML) despite salvage therapy is dismal. This phase I dose-escalation trial assessed the safety and preliminary clinical activity of selinexor, an oral exportin-1 (XPO1) inhibitor, in combination with FLAG-Ida in younger R/R AML patients. The aim was to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). Fourteen patients were included, and selinexor dosage was 60 mg (3 patients), 80 mg (3 patients), and 100 mg (7 patients) weekly. No dose-limiting toxicities were reported. Grade ≥3 non-hematologic adverse events (AEs) occurred in 78.6% of patients. Two patients were non MTD evaluable due to early death, and overall, 3 out of 14 patients (21.4%) had fatal AEs. Five out of 12 (42%) response and MTD evaluable patients achieved a complete remission (CR; n=4) or CR with incomplete hematologic recovery (CRi, n=1), and 4 patients (33%) subsequently underwent allogeneic transplantation. The median overall survival (OS) and event-free survival (EFS) were 6.0 (range 0.9-19.3) and 1.1 months (range 0.7-19.3), respectively. Using selinexor 100 mg/weekly, CR/CRi rate of 66.7%, OS 13.6 months (range, 1.6-19.3), and EFS 10.6 months (range, 0.9-19.3). At last follow-up, 3 patients were alive. Selinexor 100 mg/weekly with FLAG-Ida combination in R/R AML showed acceptable tolerability and efficacy, establishing the RP2D of this regimen in future clinical trials. ClinicalTrials.gov Identifier: NCT03661515.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hidrazinas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Triazoles/uso terapéutico , Vidarabina/análogos & derivados , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Citarabina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Idarrubicina/uso terapéutico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/uso terapéuticoRESUMEN
BACKGROUND: Information regarding impact on healthcare systems of relapsed or refractory (R/R) FLT3 mutated (FLT3mut) acute myeloid leukemia (AML) is scarce. OBJECTIVE: To assess the time and reimbursement associated with hospitalizations of patients with R/R FLT3mut AML in a tertiary Spanish hospital. METHODS: Retrospective review of medical charts identified patients aged ≥ 18 years with R/R FLT3mut AML between 1998 and 2018. Data were collected from the date of first diagnosis of R/R FLT3mut AML (index) until death or loss to follow-up. The primary end point was duration and frequency of hospitalization, use of outpatient resources and transfusion burden. Reimbursement associated with hospitalizations (including associated chemotherapy) was also assessed. RESULTS: Thirty-eight patients were eligible for inclusion. Their median age was 52 years, and 30 (79%) received intensive salvage chemotherapy; FLAG-IDA-based regimens were the most frequent (24 patients, 63%). Overall, there were 150 hospitalizations (mean 3.9/patient; mean duration 21 days). Patients spent a mean of 24% of the study period in hospital. Total mean reimbursement was 108 293 per patient; the majority (89 834) attributable to inpatient stays (22 576 /hospitalization). During chemotherapy period (prior to first alloHSCT), there were 73 hospitalizations (mean duration 22 days); mean reimbursement was 19 776 per hospitalization and 49 819 per patient. AlloHSCT (n = 16) involved 77 hospitalizations (mean duration 21 days), mean reimbursement 25 231/hospitalization and 131 515 per patient. CONCLUSION: Data from this study suggest that there is a substantial healthcare resource utilization and cost burden on R/R FLT3mut AML patients in Spain receiving active treatments.
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Recursos en Salud , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Mutación , Aceptación de la Atención de Salud , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Resistencia a Antineoplásicos , Femenino , Costos de la Atención en Salud , Hospitalización , Humanos , Reembolso de Seguro de Salud , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Recurrencia , Estudios Retrospectivos , España/epidemiología , Centros de Atención TerciariaRESUMEN
Refractoriness to induction therapy and relapse after complete remission are the leading causes of death in patients with acute myeloid leukaemia (AML). This study focussed on the prediction of response to standard induction therapy and outcome of patients with AML using a combined strategy of mutational profiling by next-generation sequencing (NGS, n = 190) and ex vivo PharmaFlow testing (n = 74) for the 10 most widely used drugs for AML induction therapy, in a cohort of adult patients uniformly treated according to Spanish PETHEMA guidelines. We identified an adverse mutational profile (EZH2, KMT2A, U2AF1 and/or TP53 mutations) that carries a greater risk of death [hazard ratio (HR): 3·29, P < 0·0001]. A high correlation was found between the ex vivo PharmaFlow results and clinical induction response (69%). Clinical correlation analysis showed that the pattern of multiresistance revealed by ex vivo PharmaFlow identified patients with a high risk of death (HR: 2·58). Patients with mutation status also ran a high risk (HR 4·19), and the risk was increased further in patients with both adverse profiles (HR 4·82). We have developed a new score based on NGS and ex vivo drug testing for AML patients that improves upon current prognostic risk stratification and allows clinicians to tailor treatments to minimise drug resistance.
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Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2) is a rare poor prognosis cytogenetic abnormality present in acute myeloid leukemia (AML) and other myeloid neoplasms. OBJECTIVE: The aim of this study was to evaluate the outcome of a cohort of 61 patients with newly diagnosed AML with inv(3)/t(3;3) treated with homogeneous intensive chemotherapy protocols conducted by the Spanish PETHEMA and CETLAM cooperative groups between 1999 and 2017. METHODS: In this retrospective study the main clinical and biologic parameters were collected. The complete response (CR) rate, the cumulative incidence of relapse (CIR) and the overall survival (OS) were calculated. An analysis of prognostic factors for survival was performed. RESULTS: Sixty-one patients received induction and only 18 (29%) achieved CR (median age, 46 years). Allogeneic hematopoietic stem cell transplantation (alloHSCT) was performed in 36 patients (59%), 15 with active disease. One- and 4-year CIR were 52% and 56%. One- and 4-year OS probabilities were 41% and 13%. By multivariate analysis monosomal karyotype (MK) was associated with poorer OS (HR 2.0, P = .017). CONCLUSION: Inv(3)/t(3;3) AML is a poor prognosis entity with low response to standard chemotherapy and to alloHSCT because of frequent and early relapse. MK was associated with a poorer prognosis. Improved therapeutic strategies are clearly needed.
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Inversión Cromosómica , Cromosomas Humanos Par 3 , Leucemia Mieloide Aguda/genética , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Cariotipificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for minimal residual disease assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-single nucleotide variants. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by sequencing, evaluating the level of mutations detected at diagnosis. The predictive value of minimal residual disease status by sequencing, multiparameter flow cytometry, or quantitative polymerase chain reaction analysis was determined by survival analysis. The sequencing method achieved a sensitivity of 10-4 for single nucleotide variants and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnostic data set). Sequencing-determined minimal residual disease positive status was associated with lower disease-free survival (hazard ratio 3.4, P=0.005) and lower overall survival (hazard ratio 4.2, P<0.001). Multivariate analysis showed that minimal residual disease positive status determined by sequencing was an independent factor associated with risk of death (hazard ratio 4.54, P=0.005) and the only independent factor conferring risk of relapse (hazard ratio 3.76, P=0.012). This sequencing-based method simplifies and standardizes minimal residual disease evaluation, with high applicability in acute myeloid leukemia. It is also an improvement upon flow cytometry- and quantitative polymerase chain reaction-based prediction of outcomes of patients with acute myeloid leukemia and could be incorporated in clinical settings and clinical trials.
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Biomarcadores de Tumor , Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Adulto , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Nucleofosmina , Polimorfismo de Nucleótido Simple , Pronóstico , Modelos de Riesgos Proporcionales , Flujo de TrabajoAsunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Leucemia Mieloide Aguda , Mutación , Sistema de Registros , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Proteínas Potenciadoras de Unión a CCAAT/genética , Pronóstico , España/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , AdultoRESUMEN
Few reports analyze the incidence and clinical outcome of invasive fungal disease (IFD) in patients with newly diagnosed acute myeloid leukemia (AML) undergoing intensive chemotherapy, and thus the impact of different antifungal prophylactic regimens remains unclear. We analyze the incidence and clinical outcome of IFD in a large series of adult AML patients undergoing front-line intensive induction and consolidation chemotherapy between 2004 and 2015 in a single institution. Three antifungal prophylaxis regimens were given (2004-2005 oral fluconazole, 2006-2012 intravenous itraconazole, and 2013-2015 voriconazole). Overall, 285 patients and 589 intensive chemotherapy episodes were assessed (47%) (induction courses 47% and consolidation 53%). The median age was 51 years (range, 17-65). We observed 56 (10%) episodes of IFD. According to the EORTC 2008 criteria, IFD was classified as possible (29, 52%), probable (17, 30%), and proven (10, 18%). Possible/probable/proven IFD rate was significantly lower during HiDAC consolidation as compared to any anthracycline-containing chemotherapy courses (2% vs. 11%, P = 0.001), and under voriconazole prophylaxis as compared to itraconazole and fluconazole (6% vs. 11% vs. 15%, P = 0.007), and the multivariate analysis showed that they were independent risk factors. Patients under voriconazole prophylaxis had shorter hospitalization duration and less frequent use of empirical or directed antifungal therapy. In conclusion, IFD was a frequent complication during upfront intensive chemotherapy courses for adult AML patients. This retrospective study shows that voriconazole prophylaxis was feasible and associated with a lower risk of IFD compared with intravenous itraconazole or oral fluconazole schedules.
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Antifúngicos/administración & dosificación , Quimioterapia de Consolidación , Infecciones Fúngicas Invasoras , Leucemia Mieloide Aguda , Adolescente , Adulto , Anciano , Femenino , Humanos , Incidencia , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/prevención & control , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The platelet-derived growth factor receptor ß (PDGFRB) gene translocations lead to a spectrum of chronic myeloid neoplasms, frequently associated with eosinophilia. Clinical heterogeneity is associated with a molecular one. Here, we report a novel case of a patient harboring a t(5;8)(q33;p22) translocation, resulting in the PCM1/PDGFRB fusion. Conventional cytogenetics and RNA sequencing were performed to identify the chromosomes and the genes involved in the rearrangement, respectively. This study shows that the combination of different strategies is pivotal to fine-tune the diagnosis and the clinical management of the patient. After 1 year of treatment with imatinib, the patient achieves hematological and molecular remission. We present an attractive strategy to identify novel and/or cryptic fusions, which will be relevant for clinicians dealing with the diagnosis of the patients with myelodysplastic syndrome/myeloproliferative diseases with atypical manifestations.
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Autoantígenos , Proteínas de Ciclo Celular , Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva , Proteínas de Fusión Oncogénica , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Análisis de Secuencia de ARN , Autoantígenos/genética , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 5/metabolismo , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Translocación GenéticaRESUMEN
BACKGROUND: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols. METHODS: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR). RESULTS: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036). CONCLUSIONS: TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.
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Biomarcadores de Tumor/genética , Janus Quinasa 2/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Receptores de Citocinas/biosíntesis , Resultado del TratamientoRESUMEN
Studies dealing with rheological red blood cell (RBC) behavior in sickle cell trait carriers are scarce. Moreover, the association with α-thalassemia (α-thal), which also modifies erythrocyte behavior, has not always been taken into account. We analyzed erythrocyte deformability by means of a shear stress diffractometer, along with hematological and biochemical parameters (glucose and plasma lipids), given their possible influence on erythrocyte deformability, in 14 sickle cell trait carriers and 23 healthy controls. Nine patients were also α-thal carriers and five were not. Among the thalassemia carriers, eight were heterozygous and one was homozygous. When compared with controls, sickle cell trait carriers showed no differences for any of the biochemical parameters analyzed (p > 0.05), but significantly lower hemoglobin (Hb) (p = 0.003), mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) (p < 0.001) levels, although no differences in erythrocyte deformability were observed at any of the shear stresses tested (p > 0.05). When comparing sickle cell trait carriers, with and without α-thal, no differences in erythrocyte deformability were observed (p > 0.05), in spite of the former showing lower MCV and MCH (p < 0.05) levels. Carriers of α-thal had lower Hb S [ß6(A3)Glu â Val; HBB: c.20A > T] levels (p = 0.013) than non carriers. The existence of a compensating mechanism seems reasonable because, despite presenting lower erythrocyte indices, which could worsen erythrocyte deformability, this rheological property improves when the percentage of Hb S is lower.
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Deformación Eritrocítica , Eritrocitos/metabolismo , Rasgo Drepanocítico/metabolismo , Talasemia alfa/metabolismo , Adulto , Sustitución de Aminoácidos , Índices de Eritrocitos , Eritrocitos/patología , Femenino , Hemoglobina Falciforme/genética , Hemoglobina Falciforme/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Rasgo Drepanocítico/genética , Rasgo Drepanocítico/patología , Talasemia alfa/genética , Talasemia alfa/patologíaRESUMEN
Cytogenetic aberrations identified by metaphase cytogenetics (MC) have diagnostic, prognostic, and therapeutic implications in myelodysplastic syndromes (MDS). However, in some MDS patients MC study is unsuccesful. Single nucleotide polymorphism array (SNP-A) based karyotyping could be helpful in these cases. We performed SNP-A in 62 samples from bone marrow or peripheral blood of primary MDS with an unsuccessful MC study. SNP-A analysis enabled the detection of aberrations in 31 (50%) patients. We used the copy number alteration information to apply the International Prognostic Scoring System (IPSS) and we observed differences in survival between the low/intermediate-1 and intermediate-2/high risk patients. We also saw differences in survival between very low/low/intermediate and the high/very high patients when we applied the revised IPSS (IPSS-R). In conclusion, SNP-A can be used successfully in PB samples and the identification of CNA by SNP-A improve the diagnostic and prognostic evaluation of this group of MDS patients.
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Cariotipificación/métodos , Síndromes Mielodisplásicos/diagnóstico , Polimorfismo de Nucleótido Simple , Médula Ósea/patología , Femenino , Dosificación de Gen , Humanos , Masculino , Síndromes Mielodisplásicos/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , PronósticoRESUMEN
Introduction: Acute lymphoblastic leukemia (ALL) is a prevalent childhood cancer with high cure rate, but poses a significant medical challenge in adults and relapsed patients. Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype, with approximately half of cases characterized by CRLF2 overexpression and frequent concomitant IKZF1 deletions. Methods: To address the need for efficient, rapid, and cost-effective detection of CRLF2 alterations, we developed a novel RT-qPCR technique combining SYBR Green and highresolution melting analysis on a single plate. Results: The method successfully identified CRLF2 expression, P2RY8::CRLF2 fusions, and CRLF2 and JAK2 variants, achieving a 100% sensitivity and specificity. Application of this method across 61 samples revealed that 24.59% exhibited CRLF2 overexpression, predominantly driven by IGH::CRLF2 (73.33%). High Resolution Melting analysis unveiled concurrent CRLF2 or JAK2 variants in 8.19% of samples, as well as a dynamic nature of CRLF2 alterations during disease progression. Discussion: Overall, this approach provides an accurate identification of CRLF2 alterations, enabling improved diagnostic and facilitating therapeutic decision-making.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Proteínas WT1/biosíntesis , Adolescente , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual , Medición de Riesgo , Factores de Riesgo , España/epidemiología , Proteínas WT1/genéticaRESUMEN
Chromosomal translocations in hematological malignancies often result in novel fusion chimeric genes. We report a case of acute myeloid leukemia with a clonal translocation t(11;12)(p15;q13) displaying morphologic and immunophenotypic features resembling the classical hypergranular subtype of acute promyelocytic leukemia. The gene fused to NUP98 (nucleoporin 98) was detected by comparative genomic hybridization array as the retinoid acid receptor gamma gene (RARG). The involvement of RARG in a chimeric fusion transcript has not been reported previously in human leukemia.
Asunto(s)
Fusión Génica , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Receptores de Ácido Retinoico/genética , Adulto , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 12/genética , Hibridación Genómica Comparativa , Diagnóstico Diferencial , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Translocación Genética , Receptor de Ácido Retinoico gammaRESUMEN
Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, copy number variants, and loss of heterozygosity) in a single workflow. In this study, peripheral blood samples from a series of 21 myelofibrosis patients were analyzed via OGM. We assessed the clinical impact of the application of OGM for disease risk stratification using the DIPSS-plus, GIPSS, and MIPSS70+v2 prognostic scores compared with the standard-of-care approach. OGM, in combination with NGS, allowed for risk classification in all cases, compared to only 52% when conventional techniques were used. Cases with unsuccessful karyotypes (n = 10) using conventional techniques were fully characterized using OGM. In total, 19 additional cryptic aberrations were identified in 9 out of 21 patients (43%). No alterations were found via OGM in 4/21 patients with previously normal karyotypes. OGM upgraded the risk category for three patients with available karyotypes. This is the first study using OGM in myelofibrosis. Our data support that OGM is a valuable tool that can greatly contribute to improve disease risk stratification in myelofibrosis patients.