RESUMEN
CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.
Asunto(s)
Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Antígenos CD19/uso terapéutico , Síndrome de Liberación de Citoquinas , Humanos , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Estudios Prospectivos , Reino Unido/epidemiologíaRESUMEN
With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.
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Anemia/complicaciones , Anemia/terapia , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/complicaciones , Neumonía Viral/prevención & control , Transfusión Sanguínea , Trasplante de Médula Ósea , COVID-19 , Infección Hospitalaria/prevención & control , Humanos , SARS-CoV-2Asunto(s)
Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/inmunología , Resultado del Tratamiento , Masculino , FemeninoAsunto(s)
Anemia/diagnóstico , Betacoronavirus , Infecciones por Coronavirus/diagnóstico , Hemoglobinopatías/diagnóstico , Neumonía Viral/diagnóstico , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/epidemiología , COVID-19 , Niño , Preescolar , Infecciones por Coronavirus/epidemiología , Femenino , Hemoglobinopatías/epidemiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/epidemiología , SARS-CoV-2 , Adulto JovenRESUMEN
The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that â¼ 43% of all mixed lineage leukemia (MLL)-rearranged leukemias are EVI1(pos). High EVI1 expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELL fusion genes. In addition, we present evidence that EVI1(pos) MLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1(neg) MLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1 expression on transformation of Evi1(pos) HSCs. MLL-AF9 does not activate Evi1 expression in MLL-AF9-transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1(neg). Moreover, shRNA-mediated knockdown of Evi1 in an Evi1(pos) MLL-AF9 mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1 provides a growth-promoting signal. Using the Evi1(pos) MLL-AF9 mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1 expression. We conclude that EVI1 is a critical player in tumor growth in a subset of MLL-rearranged AMLs.
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Proteínas de Unión al ADN/metabolismo , Reordenamiento Génico/genética , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/metabolismo , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Proliferación Celular , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 11/genética , Ensayo de Unidades Formadoras de Colonias , Proteínas de Unión al ADN/genética , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/etiología , Lisina/metabolismo , Proteína del Locus del Complejo MDS1 y EV11 , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Proto-Oncogenes Mas , Proto-Oncogenes/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/genéticaRESUMEN
Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll-AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes.
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Transformación Celular Neoplásica/genética , Redes Reguladoras de Genes/genética , Leucemia/genética , Mutagénesis Insercional , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Proteínas de Fusión Oncogénica/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Análisis Mutacional de ADN/métodos , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Leucemia/patología , Ratones , Ratones Endogámicos C57BL , Mutagénesis Insercional/fisiología , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Células U937RESUMEN
INTRODUCTION: Sickle cell disease (SCD) is an inherited disorder characterised by polymerisation of deoxygenated haemoglobin S and microvascular obstruction. The cardinal feature is generalised pain referred to as vaso-occlusive crises (VOC), multi-organ damage and premature death. SCD is the most prevalent inherited life-threatening disorders in the world and over 85% of world's 400,000 annual births occur low-and-middle-income countries. Hydroxyurea remained the only approved disease modifying therapy (1998) until the FDA approved L-glutamine (2017), Crizanlizumab and Voxelotor (2019) and gene therapies (Exa-cel and Lovo-cel, 2023). AREAS COVERED: Clinical trials performed in the last 10 years (November 2013 - November 2023) were selected for the review. They were divided according to the mechanisms of drug action. The following pubmed central search terms [sickle cell disease] or [sickle cell anaemia] Hydroxycarbamide/ Hydroxyurea, L-Glutamine, Voxelotor, Crizanlizumab, Mitapivat, Etavopivat, gene therapy, haematopoietic stem cell transplantation, and combination therapy. EXPERT OPINION: We recommend future trials of combination therapies for specific complications such as VOCs, chronic pain and renal impairment as well as personalised medicine approach based on phenotype and patient characteristics. Following recent approval of gene therapy for SCD, the challenge is addressing the role of shared decision-making with families, global access and affordability.
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Anemia de Células Falciformes , Benzaldehídos , Dolor Crónico , Pirazinas , Pirazoles , Humanos , Hidroxiurea/uso terapéutico , Glutamina/uso terapéutico , Anemia de Células Falciformes/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Combinación de MedicamentosRESUMEN
The acute pain crisis (APC) is the commonest complication of sickle cell disease (SCD). Severe episodes may require treatment in hospital with strong opioid analgesic drugs, combined with additional supportive care measures. Guidelines for APC management have been produced over the past two decades gathering evidence from published studies, expert opinion, and patient perspective. Unfortunately, reports from multiple sources indicate that guidelines are often not followed, and that acute care in emergency departments and on acute medical wards is suboptimal. It is important to understand what leads to this breakdown in health care, and to identify evidence-based interventions which could be implemented to improve care. This review focuses on recently published articles as well as information about on-going clinical trials. Aspects of care which could potentially make a difference to patient experience include availability and accessibility of individual care plans agreed between patient and treating specialist, innovative means of delivering initial opioids to reduce time to first analgesia, and availability of a specialist unit away from the ED, where expert care can be delivered in a more compassionate environment. The current evidence of improved outcomes and health economic advantage with these interventions is inadequate, and this is hampering their implementation into health care systems.
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Dolor Agudo , Anemia de Células Falciformes , Humanos , Dolor Agudo/diagnóstico , Dolor Agudo/etiología , Dolor Agudo/terapia , Manejo del Dolor/efectos adversos , Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/tratamiento farmacológicoRESUMEN
DNA methylation patterns are frequently dysregulated in cancer, although little is known of the mechanisms through which specific gene sets become aberrantly methylated. The ecotropic viral integration site 1 (EVI1) locus encodes a DNA binding zinc-finger transcription factor that is aberrantly expressed in a subset of acute myeloid leukemia (AML) patients with poor outcome. We find that the promoter DNA methylation signature of EVI1 AML blast cells differs from those of normal CD34(+) bone marrow cells and other AMLs. This signature contained 294 differentially methylated genes, of which 238 (81%) were coordinately hypermethylated. An unbiased motif analysis revealed an overrepresentation of EVI1 binding sites among these aberrantly hypermethylated loci. EVI1 was capable of binding to these promoters in 2 different EVI1-expressing cell lines, whereas no binding was observed in an EVI1-negative cell line. Furthermore, EVI1 was observed to interact with DNA methyl transferases 3A and 3B. Among the EVI1 AML cases, 2 subgroups were recognized, of which 1 contained AMLs with many more methylated genes, which was associated with significantly higher levels of EVI1 than in the cases of the other subgroup. Our data point to a role for EVI1 in directing aberrant promoter DNA methylation patterning in EVI1 AMLs.
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Metilación de ADN , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Regiones Promotoras Genéticas/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Western Blotting , Inmunoprecipitación de Cromatina , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , ADN de Neoplasias/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de Transcripción/metabolismo , Adulto Joven , ADN Metiltransferasa 3BRESUMEN
Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting crossresistance to prednisolone, vincristine, asparaginase, and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37% +/- 13% 5 year DFS).
Asunto(s)
Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Edad , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Asparaginasa/farmacología , Asparaginasa/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Niño , Análisis por Conglomerados , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Daunorrubicina/farmacología , Daunorrubicina/uso terapéutico , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Homeodominio/genética , Humanos , Mercaptopurina/farmacología , Recurrencia Local de Neoplasia , Proteínas de Fusión Oncogénica/genética , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Valor Predictivo de las Pruebas , Prednisolona/farmacología , Prednisolona/uso terapéutico , Análisis de Componente Principal , Modelos de Riesgos Proporcionales , Translocación Genética/genética , Resultado del Tratamiento , Células Tumorales Cultivadas , Vincristina/farmacología , Vincristina/uso terapéuticoRESUMEN
Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were recently demonstrated in acute myeloid leukemia (AML), but their prevalence and prognostic impact remain to be explored in large extensively characterized AML series, and also in various other hematologic malignancies. Here, we demonstrate in 893 newly diagnosed cases of AML mutations in the IDH1 (6%) and IDH2 (11%) genes. Moreover, we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias (n = 96), a single case of acute lymphoblastic leukemia (n = 96), and none in chronic myeloid leukemias (n = 81). In AML, IDH1 and IDH2 mutations are more common among AML with normal karyotype and NPM1(mutant) genotypes. IDH1 mutation status is an unfavorable prognostic factor as regards survival in a composite genotypic subset lacking FLT3(ITD) and NPM1(mutant). Thus, IDH1 and IDH2 mutations are common genetic aberrations in AML, and IDH1 mutations may carry prognostic value in distinct subtypes of AML.
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Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Mutación , Adolescente , Adulto , Anciano , Femenino , Enfermedades Hematológicas , Humanos , Janus Quinasa 2/genética , Leucemia Mieloide Aguda/clasificación , Masculino , Persona de Mediana Edad , Nucleofosmina , Prevalencia , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Chimeric antigen receptor-modified T-cells targeting CD19 (CAR-T19) are licensed for treating relapsed/refractory diffuse large B-cell lymphoma and B-acute lymphoblastic leukemia. Predicting treatment responses and toxicity (e.g., cytokine release syndrome and neurotoxicity) remains a big challenge. CAR-T19 monitoring could increase our understanding of treatment responses and be of relevance to patient management. A robust method for accurate CAR-T19 detection is therefore extremely desirable. METHODS: An assay that uses fluorochrome-conjugated human recombinant soluble CD19 was tested against two commercially available CAR-T19 therapies and a CAR-T19 cell line developed in-house. Precision, concordance, and analyte stability were tested using peripheral blood obtained from CAR-T19-treated patients and controls. RESULTS: The assay showed good accuracy, and had a limit of blank for whole blood samples of 0.13%. Reproducibility and inter-operator concordance were satisfactory (CVs <15%). The assay distinguished CAR-T19 from reactive T-cells in cerebrospinal fluid (CSF) from patients with suspected immune effector cell-associated neurotoxicity syndrome (ICANS), and was adapted to study memory T-cell compartments in treated patients. CONCLUSION: The assay enabled routine monitoring of CAR-T19 in blood and CSF samples. Despite profound cytopenia in many lymphoma patients, results were obtained regularly from only 4 ml of blood. The assay can be adapted easily to characterize the memory and exhaustion status of CAR-T19 and native T-cells. Importantly, it does not rely on CAR construct specificity; thus, it can be used to detect any CD19-targeted CAR cell. Finally, our validation process can serve as a blueprint for other fluorochrome proteins used to detect CAR cells.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Antígenos CD19 , Citometría de Flujo , Humanos , Inmunoterapia Adoptiva/métodos , Laboratorios , Linfoma de Células B Grandes Difuso/diagnóstico , Receptores de Antígenos de Linfocitos T , Reproducibilidad de los ResultadosRESUMEN
We examined the gene expression profiles of two independent cohorts of patients with acute myeloid leukemia [n=247 and n=214 (younger than or equal to 60 years)] to study the applicability of gene expression profiling as a single assay in prediction of acute myeloid leukemia-specific molecular subtypes. The favorable cytogenetic acute myeloid leukemia subtypes, i.e., acute myeloid leukemia with t(8;21), t(15;17) or inv(16), were predicted with maximum accuracy (positive and negative predictive value: 100%). Mutations in NPM1 and CEBPA were predicted less accurately (positive predictive value: 66% and 100%, and negative predictive value: 99% and 97% respectively). Various other characteristic molecular acute myeloid leukemia subtypes, i.e., mutant FLT3 and RAS, abnormalities involving 11q23, -5/5q-, -7/7q-, abnormalities involving 3q (abn3q) and t(9;22), could not be correctly predicted using gene expression profiling. In conclusion, gene expression profiling allows accurate prediction of certain acute myeloid leukemia subtypes, e.g. those characterized by expression of chimeric transcription factors. However, detection of mutations affecting signaling molecules and numerical abnormalities still requires alternative molecular methods.
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Regulación Neoplásica de la Expresión Génica/genética , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Femenino , Perfilación de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Nucleofosmina , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).
Asunto(s)
Biomarcadores de Tumor/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Nucleofosmina , PronósticoRESUMEN
PURPOSE The purpose of this study was to investigate frequency and prognostic significance of high EVI1 expression in acute myeloid leukemia (AML). PATIENTS AND METHODS A diagnostic assay detecting multiple EVI1 splice variants was developed to determine the relative EVI1 expression by single real-time quantitative polymerase chain reaction in 1,382 newly diagnosed adult patients with AML younger than 60 years. Patients were treated on four Dutch-Belgian HOVON (n = 458) and two German-Austrian AML Study Group protocols (n = 924). Results The EVI1 assay was tested in the HOVON cohort and validated in the AMLSG cohort. High EVI1 levels (EVI1(+)) were found with similar frequencies in both cohorts combined, with a 10.7% incidence (148 of 1,382). EVI1(+) independently predicted low complete remission (CR) rate (odds ratio, 0.54; P = .002), adverse relapse-free survival (RFS; hazard ratio [HR], 1.32; P = .05), and event-free survival (EFS; HR, 1.46; P < .001). This adverse prognostic impact was more pronounced in the intermediate cytogenetic risk group (EFS; HR, 1.64; P < .001; and RFS; HR, 1.55; P = .02), and was also apparent in cytogenetically normal AML (EFS; HR, 1.67; P = .008). Besides inv(3)/t(3;3), EVI1(+) was significantly associated with chromosome abnormalities monosomy 7 and t(11q23), conferring prognostic impact within these two cytogenetic subsets. EVI1(+) was virtually absent in favorable-risk AML and AML with NPM1 mutations. Patients with EVI1(+) AML (n = 28) who received allogeneic stem cell transplantation in first CR had significantly better 5-year RFS (33% +/- 10% v 0%). CONCLUSION EVI1 expression in AML is unequally distributed in cytogenetic subtypes. It predicts poor outcome, particularly among intermediate cytogenetic risk AML. Patients with EVI1(+) AML may benefit from allogeneic transplantation in first CR. Pretreatment EVI1 screening should be included in risk stratification.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 7 , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Monosomía , Proto-Oncogenes/genética , Factores de Transcripción/genética , Translocación Genética , Adolescente , Adulto , Análisis Citogenético , Supervivencia sin Enfermedad , Europa (Continente) , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Modelos Logísticos , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Nucleofosmina , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Trasplante de Células Madre , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Regulación hacia Arriba , Adulto JovenRESUMEN
PURPOSE: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved. PATIENTS AND METHODS: Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction. RESULTS: 3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3). CONCLUSION: Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inversión Cromosómica , Cromosomas Humanos Par 3 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Moléculas de Adhesión Celular/metabolismo , Aberraciones Cromosómicas , Ensayos Clínicos como Asunto , Proteínas de Unión al ADN , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Genes ras , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Cariotipificación , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Monosomía , Análisis Multivariante , Mutación , Proteínas de Neoplasias/metabolismo , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Proto-Oncogenes , Inducción de Remisión , Factores de Transcripción , Translocación Genética , Resultado del TratamientoRESUMEN
Inappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6% of cases (n = 32), whereas 7.8% were EVI1(+) (n = 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR = 1.9; P = .002) and disease-free survival (HR = 2.1, P = .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1(+) cases that lacked expression of ME (EVI1(+)ME(-); n = 17) from cases that were ME(+) (EVI1(+)ME(+); n = 24). The atypical EVI1(+)ME(-) expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1(+)ME(-) cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1(+)ME(+) group. EVI1(+)ME(-) expression predicts an extremely poor prognosis distinguishable from the general EVI1(+) AML patients (overall survival [OS]: P < .001 and event-free survival [EFS]: P = .002). We argue that EVI1/ME quantitative expression analysis should be implemented in the molecular diagnostic procedures of AML.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 3/genética , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/patología , Proto-Oncogenes/genética , Factores de Transcripción/genética , Adulto , Anciano , Empalme Alternativo/genética , Estudios de Cohortes , Análisis Citogenético , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Análisis de Supervivencia , Factores de Transcripción/metabolismo , Resultado del TratamientoRESUMEN
Over the past four decades, treatment of acute leukemia in children has made remarkable progress, from this disease being lethal to now achieving cure rates of 80% for acute lymphoblastic leukemia and 45% for acute myeloid leukemia. This progress is largely owed to the optimization of existing treatment modalities rather than the discovery of new agents. However, the annual number of patients with leukemia who experience relapse after initial therapy remains greater than that of new cases of most childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize medications and tailor treatment regimens to individual patients, with the goal of enhancing efficacy and safety through better understanding of the person's genetic makeup. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute leukemia. These include work using candidate-gene approaches, as well as genome-wide studies using haplotype mapping and gene expression profiling. These strategies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm.