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Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
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Dioxigenasas , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Azacitidina , Leucemia Mieloide Aguda/genética , Estimación de Kaplan-Meier , Mutación , Proteínas de Unión al ADN/genética , Dioxigenasas/genéticaRESUMEN
BACKGROUND: Flow cytometry (FCM) is a co-criterion in myelodysplastic syndromes (MDS) diagnostics according to the WHO classification. The presented study compared diagnostic power and prognostic impact of different FCM-based scores. METHODS: A total of 807 bone marrow (BM) samples of patients with cytopenia (543 MDS, 153 non-clonal cytopenias, 111 non-MDS myeloid malignancies) and 78 healthy controls have been investigated using a standardized 8-color-FCM procedure. FCSS, Ogata-score, iFS, RED-score, and ELN-NEC were analyzed for sensitivity and specificity in comparison to standard diagnostic tools. Median follow up for patients was 26 month (range: 0.2-89). RESULTS: The iFS showed the highest accuracy (80%) with the best balance between sensitivity (79%) and specificity (86%). This was also valid in MDS with very low IPSS-R and even in MDS without ring sideroblasts, with normal blast count and karyotype, where iFS could confirm diagnosis in 62% and 65% of patients. Besides the high diagnostic power, the established iFS category "consistent with MDS" was associated with inferior overall survival (OS) independent from WHO classification (median: 51 month vs. not reached, p < 0.0001). Remarkably, this iFS category redefined a subgroup of patients with worse OS within IPSS-R low-risk category (73 month vs. not reached, p = 0.0433). Finally, multivariable analysis showed that iFS added independent prognostic information regarding OS besides IPSS-R. CONCLUSIONS: The iFS separates non-clonal cytopenias and MDS with the highest accuracy, provided information in addition to standard diagnostic procedures, and refined established prognostic tools for outcome prediction.
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Síndromes Mielodisplásicos , Humanos , Pronóstico , Citometría de Flujo/métodos , Síndromes Mielodisplásicos/patología , Cariotipo , CariotipificaciónRESUMEN
BACKGROUND: Lysyl oxidase (LOX) has been described as necessary for premetastatic niche formation in epithelium-derived malignancies and its expression level therefore correlates with risk of metastatic disease and overall survival. However, its role in acute myeloid leukemia (AML) has not been sufficiently analyzed. METHODS: We investigated LOX plasma expression in 683 AML patients (age 17-60 years) treated within the prospective AML2003 trial (NCT00180102). The optimal cut-off LOX value was determined using a minimal-p-value method dichotomizing patients into a LOX-high group (> 109 ng/mL, n = 272, 40%) and a LOX-low group (≤ 109 ng/mL, n = 411, 60%). RESULTS: Higher LOX expression was associated with lower peripheral white blood cells, lower serum LDH, and a lower frequency of FLT3-ITD and NPM1 mutations at diagnosis. Higher LOX expression was found significantly more frequently in patients with secondary AML and therapy-related AML, in patients with French-American-British M5 subtypes, and in patients with adverse-risk cytogenetics. Comparing patients in the LOX-high group and the LOX-low group revealed a 3-year overall survival (OS) of 47 and 53% (p = 0.022) and 3-year event-free survival (EFS) of 27 and 35% (p = 0.005), respectively. In the LOX-high group significantly more patients had extramedullary AML compared to the LOX-low group (p = 0.037). Combining extramedullary AML and LOX as interacting factors in a multivariate analysis resulted in an independent impact on survival for the LOX-high-extramedullary interaction for OS (HR = 2.25, p = 0.025) and EFS (HR = 2.48, p = 0.008). Furthermore, in patients with extramedullary disease (n = 59) the LOX level predicted survival. Patients within the LOX-low group had an OS of 43% and EFS of 36% as compared to the LOX-high group with an OS of 13% and EFS of 6% (p = 0.002 and p = 0.008, respectively). CONCLUSION: We hypothesize LOX expression to be a new potential biomarker to predict outcome in AML, specifically in AML subgroups such as the prognostic heterogeneous group of AML patients with extramedullary disease. TRIAL REGISTRATION: This retrospective study was performed with patient samples registered within the prospective AML2003 trial (NCT00180102). Patients were enrolled between December 2003 and November 2009.
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INTRODUCTION: Acute myeloid leukemia (AML) rarely involves the central nervous system (CNS). Little is known about the clinical course in adult AML patients since most studies examined pediatric patients. Therefore, this study analyzed the data of patients treated in three prospective trials of the "Study Alliance Leukemia" (SAL) study group for CNS involvement. METHODS: In all, 3,261 AML patients included in the prospective AML96, AML2003, and AML60+ trials of the SAL study group were analyzed. Symptomatic patients underwent cerebrospinal fluid (CSF) puncture and CNS involvement was diagnosed depending on morphology and/or flow cytometry of the CSF. Cytogenetic, molecular, clinical, and laboratory parameters were analyzed in order to identify risk factors. RESULTS: A total of 55 patients had proven symptomatic CNS involvement. Significantly more patients revealed CNS involvement at relapse (34 patients, 2.9%) compared with first diagnosis (21 patients, 0.6%), p<0.001. CNS involvement at initial diagnosis had a significantly higher frequency in patients with complex aberrant karyotypes, high serum lactate dehydrogenase activity, French-American-British M5 subtype, FLT3-internal tandem duplication (ITD) mutations alone, and co-occurrence of a FLT3-ITD and NPM1 mutation. Furthermore, AML patients with CNS involvement at diagnosis had an inferior outcome compared with patients without CNS involvement even if treated with intrathecal chemotherapy with an overall survival of 11% versus 30% at 5 years, p=0.004. CONCLUSION: This study analyzed the largest data set of adult AML patients with proven CNS involvement reported so far. The data demonstrated very low prevalence of CNS involvement at initial diagnosis in adult patients with AML, and described new risk factors. In patients with risk factors, intense diagnostic and treatment strategies should be employed in the future.
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Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes, P < .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission + complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features.
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Biomarcadores de Tumor/genética , Cromotripsis , Leucemia Mieloide Aguda/genética , Cariotipo Anormal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Hibridación Genómica Comparativa , Supervivencia sin Enfermedad , Femenino , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Cariotipificación , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
Lenalidomide (LEN) leads to erythroid improvement in the majority of patients with myelodysplastic syndrome and isolated deletion of the long arm of chromosome 5 (MDS-del(5q)). This effect is believed to be exerted via its immunomodulatory properties, although the precise nature is still incompletely understood. We prospectively performed immune profiling in the bone marrow and blood of MDS-del(5q) patients undergoing LEN therapy for a median of 6 cycles. Therapy with LEN led to a significant increase in the median absolute lymphocyte count (1.3-fold, p = 0.013) without changes in the distribution of the T helper cells within the entire compartment. In parallel, the frequency of Treg increased significantly during treatment both in the peripheral blood (5.0 vs. 9.6 %, p = 0.001) and bone marrow (3.4 vs. 8.1 %, p = 0.001). Surprisingly, LEN treatment led to a decrease in TGFbeta levels, both in the peripheral blood (4.9 vs. 2.3 ng/ml, p = 0.039) and bone marrow (4.5 vs. 0.8 ng/ml, p = 0.023). These changes were not associated with an increase in pro-inflammatory Th17 cells. Taken together, our results demonstrate that LEN induces a shift in lymphocytic populations towards immunosuppression in MDS-del(5q) patients.
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Anemia Macrocítica/tratamiento farmacológico , Factores Inmunológicos/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Talidomida/análogos & derivados , Anciano , Anciano de 80 o más Años , Anemia Macrocítica/genética , Anemia Macrocítica/inmunología , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 5/inmunología , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Lenalidomida , Masculino , Persona de Mediana Edad , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Talidomida/farmacología , Talidomida/uso terapéutico , Factor de Crecimiento Transformador beta/sangreRESUMEN
Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.
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Genes p53/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Mutación , Adolescente , Adulto , Anciano , Aberraciones Cromosómicas , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Humanos , Leucemia Mieloide Aguda/terapia , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The combination of all-trans retinoic acid (ATRA) and idarubicin (AIDA) for induction therapy followed by three cycles of risk-adapted consolidation cycles is considered standard of care for patients with acute promyelocytic leukemia (APL). We report the outcome of 141 patients (median age 51 years; range, 19-82, 31 % ≥60 years) enrolled into the prospective Study Alliance Leukemia (SAL)-AIDA2000 trial, which comprised AIDA-based induction followed by only two courses of risk-adapted consolidation (daunorubicin or mitoxantrone ± cytarabine) followed by 2-year maintenance treatment. The early death rate was 7 % (median age 66 years), and additional 9 % stopped further treatment after induction. The estimated 6-year disease-free survival (DFS) was 80 % in all patients, 84 % in patients ≤60 and 72 % in patients >60 years (p = 0.140). No significant survival differences were observed between the high-risk and the non-high-risk patients (6-year OS 78 vs. 81 %, p = 0.625). Our results confirm the efficacy of a risk-adapted approach in APL patients. Furthermore, long-term outcomes are comparable to the results obtained with three cycles of consolidation. A modification of the number and intensity of conventional consolidation treatment may be a less toxic but equally effective approach and should be considered for further evaluation in randomized clinical trials in APL.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia de Consolidación/métodos , Idarrubicina/administración & dosificación , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Humanos , Leucemia Promielocítica Aguda/mortalidad , Masculino , Persona de Mediana Edad , Medicina de Precisión , Riesgo , Análisis de Supervivencia , Adulto JovenAsunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 5 , Factores Inmunológicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/análogos & derivados , Antígenos CD/genética , Antígenos CD/inmunología , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/patología , Estudios de Cohortes , Monitoreo de Drogas , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Lenalidomida , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/patología , Masculino , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Células Mieloides/patología , Talidomida/uso terapéuticoRESUMEN
Patients with acute myeloid leukemia (AML) and abnormalities of chromosome 17p (abnl(17p)) are at high-risk of treatment failure. Poor outcomes have been reported with conventional chemotherapy. To accurately define the outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with abnl(17p) AML, we analyzed the results of patients with this abnormality who received an allogeneic HSCT between January 2000 and December 2010 in 1 of 4 well-defined cohorts (Fred Hutchinson Cancer Research Center, Haemato Oncology Foundation for Adults in the Netherlands, Study Alliance Leukemia, German Cooperative Transplant Study Group). Data of 201 patients with a median age of 54 years were evaluable. At the time of analysis, 30 patients were alive with a median follow-up of 30 months. The 3-year probability of overall survival (OS) was 15% (95% confidence interval [CI], 10-20). The cumulative incidence of relapse at 3 years was 49% (95% CI, 42-56). Notably, almost 70% of all relapses occurred within the first 6 months after HSCT. Patients who were transplanted in first complete remission (CR1) had superior OS compared with those with advanced disease (22% vs 9%, P < .001). Our findings confirm the high-risk of treatment failure in abnl(17p) AML even after allogeneic HSCT in CR1. Although allogeneic HSCT remains a valid option in CR1, alternative treatment strategies are needed for the remaining patients.
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Aberraciones Cromosómicas , Cromosomas Humanos Par 17/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide/genética , Leucemia Mieloide/cirugía , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Evaluación del Resultado de la Atención al Paciente , Inducción de Remisión , Estudios Retrospectivos , Factores de Tiempo , Trasplante Homólogo , Adulto JovenRESUMEN
PURPOSE: In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics. PATIENTS AND METHODS: This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy. RESULTS: Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for ≥ three subclones, a branched pattern prevailed. In non-core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses. CONCLUSION: Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML.
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Cariotipificación/métodos , Leucemia Mieloide Aguda/genética , Metafase/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aberraciones Cromosómicas , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
The contribution of the bone marrow microenvironment in myelodysplastic syndrome is controversial. We therefore analyzed the functional properties of primary mesenchymal stromal cells from patients with myelodysplastic syndrome in the presence or absence of lenalidomide. Compared to healthy controls, clonality and growth were reduced across all disease stages. Furthermore, differentiation defects and particular expression of adhesion and cell surface molecules (e.g. CD166, CD29, CD146) were detected. Interestingly, the levels of stromal derived factor 1-alpha in patients' cells culture supernatants were almost 2-fold lower (P<0.01) than those in controls and this was paralleled by a reduced induction of migration of CD34(+) hematopoietic cells. Co-cultures of mesenchymal stromal cells from patients with CD34(+) cells from healthy donors resulted in reduced numbers of cobblestone area-forming cells and fewer colony-forming units. Exposure of stromal cells from patients and controls to lenalidomide led to a further reduction of stromal derived factor 1-alpha secretion and cobblestone area formation, respectively. Moreover, lenalidomide pretreatment of mesenchymal stromal cells from patients with low but not high-risk myelodysplastic syndrome was able to rescue impaired erythroid and myeloid colony formation of early hematopoietic progenitors. In conclusion, our analyses support the notion that the stromal microenvironment is involved in the pathophysiology of myelodysplastic syndrome thus representing a potential target for therapeutic interventions.
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Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/fisiología , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Talidomida/análogos & derivados , Anciano , Proliferación Celular/efectos de los fármacos , Técnicas de Cocultivo , Estudios de Cohortes , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Talidomida/farmacología , Talidomida/uso terapéuticoRESUMEN
The role of allogeneic stem cell transplantation (HSCT) as compared to chemotherapy in acute myeloid leukaemia (AML) patients with abnormalities of chromosome 17p [abnl(17p)] has not yet been defined. Therefore, we analysed 3530 AML patients treated in three randomized, prospective, controlled clinical trials and compared post-remission therapies using a multivariate Cox regression analysis to determine whether allogeneic HSCT is superior than chemotherapy in overcoming the detrimental impact of patients with abnl(17p) AML. One hundred and forty-three patients (4%) were identified with abnl(17p) AML. All patients had received intensive induction chemotherapy. Forty-seven patients with a median age of 54 years (18-69 years) proceeded to allogeneic HSCT in first or second remission. The 3-year overall survival (OS) rate for the entire cohort of patients was 4% [95% confidence interval (CI), 1-7%]. OS and event-free survival at 3 years, calculated from the day of HSCT, was 11% (95% CI, 2-20%) and 6% (95% CI, 0-13%), respectively. Multivariate Cox regression analysis showed no benefit of allogeneic HSCT compared to chemotherapy (Hazard Ratio 0·97, 95% CI 0·56-1·67, P = 0·9). In conclusion, allogeneic HSCT does not improve survival in patients with abnl(17p) AML as compared to other adverse cytogenetic risk abnormalities.
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Cariotipo Anormal , Cromosomas Humanos Par 17/genética , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
The European LeukemiaNet classification combines a heterogeneous group of aberrations as adverse-risk abnormalities. Our goal was to investigate the outcomes associated with distinct high-risk chromosomal abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). We performed a retrospective cohort analysis in patients with high-risk AML who received first, HLA-compatible, allogeneic HSCT between January 2005 and December 2008. Data from 236 patients with a median age of 55 years were included. Because complex karyotype (CK), -5/5q-, and abnl(17p) are overlapping categories, a hierarchical classification system based on the presence or absence of abnl(17p) and -5/5q- was developed. Patients with abnl(17p) had a 2-year event-free survival (EFS) of 11% (95% confidence interval [CI], 0%-25%), patients with -5/5q- but no abnl(17p) a 2-year EFS of 29% (95% CI, 14%-44%), and patients with adverse-risk AML but neither of the 2 marker lesions a 2-year EFS of 49% (95% CI, 39%-59%). Notably, complex and monosomal karyotypes lost their prognostic value when these marker lesions were excluded. In conclusion, hierarchical classification of adverse-risk karyotypes by 2 marker lesions, abnl(17p) and -5/5q-, is effective in prognostication of the outcome of allogeneic HSCT in AML.
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Aberraciones Cromosómicas , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 5/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Adulto , Anciano , Femenino , Antígenos HLA , Humanos , Cariotipificación , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenAsunto(s)
Anemia Perniciosa/diagnóstico , Anemia Perniciosa/patología , Aberraciones Cromosómicas , Anemia Perniciosa/etiología , Anemia Perniciosa/fisiopatología , Células de la Médula Ósea/patología , Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Recurrencia , Inducción de Remisión , Índice de Severidad de la Enfermedad , Síncope/etiología , Vitamina B 12/uso terapéutico , Deficiencia de Vitamina B 12/tratamiento farmacológico , Deficiencia de Vitamina B 12/fisiopatologíaRESUMEN
BACKGROUND: Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) leaves few therapeutic options, and mechanisms of immune escape of recurring leukemic cells remain poorly understood. Recently, acquired loss of mismatched human leukocyte antigen (HLA) was demonstrated in patients with AML undergoing haploidentical allogeneic HSCT and was suggested not to occur in HLA-matched HSCT. We hypothesized that this mechanism applies to extramedullary AML relapse which occurs frequently after allogeneic HSCT and might also not be restricted to haploidentical HSCT. METHODS: DNA from extramedullary AML relapse after HSCT was compared with bone marrow at diagnosis with array comparative genomic hybridization to investigate relapse-specific genomic aberrations in relapsing AML after allogeneic HSCT. Formalin-fixed, paraffin-embedded tissues from the same points of time were assessed for HLA, major histocompatibility complex class I chain-related gene A, and TAP2 immunohistochemistry staining to assess cell surface expression of deleted loci encoded on chromosome 6p. RESULTS: Array comparative genomic hybridization revealed a partial loss of chromosome 6p in extramedullary myeloid sarcoma relapse of AML after sustained complete remission was achieved through matched related allogeneic HSCT. Among others, a deleted region 6p21.32-p21.33, which included several HLA class I genes, was detected. CONCLUSIONS: These results suggest that the loss of HLA class I haplotype also occurs in AML relapse after HLA-matched related HSCT. Partial loss of several HLA class I genes and subsequent reduced presentation of minor histocompatibility antigens and reduced ligation of activating natural killer-cell receptors may explain the loss of graft-versus-leukemia response and extramedullary AML relapse in tissue with reduced immunologic surveillance.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Evolución Clonal/genética , Eliminación de Gen , Antígenos HLA/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/cirugía , Sarcoma Mieloide/genética , Escape del Tumor/genética , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATP , Transportadoras de Casetes de Unión a ATP/análisis , Adulto , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Hibridación Genómica Comparativa , Femenino , Predisposición Genética a la Enfermedad , Efecto Injerto vs Leucemia/genética , Haplotipos , Antígenos de Histocompatibilidad Clase I/análisis , Humanos , Inmunohistoquímica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Medición de Riesgo , Factores de Riesgo , Sarcoma Mieloide/inmunología , Sarcoma Mieloide/patología , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
PURPOSE: The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients. PATIENTS AND METHODS: Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial. Patients were assigned to the proposed genetic groups from the ELN recommendations, and survival analyses were performed using the Kaplan-Meier method and log-rank test for significance testing. RESULTS: The median age of all patients was 67 years. With a median follow-up of 8.3 years, significant differences between all risk categories were observed in patients age ≤ 60 years regarding the time to relapse, relapse-free survival, and overall survival (OS). Patients in the IR-II group had a better prognosis than patients in the IR-I group. The median OS times in young patients with favorable risk (FR), IR-I, IR-II, and adverse risk (AR) were 5.3, 1.1, 1.6, and 0.5 years, respectively. Separate analyses in the age group older than 60 years revealed significant differences between FR, AR, and IR as a whole, but not between IR-I and IR-II. CONCLUSION: In younger patients with AML, the ELN classification seems to be the best available framework for prognostic estimations to date. Caution is advised concerning its use for prospective treatment allocation before it has been prospectively validated. In elderly patients, alternative prognostic factors are desirable for further risk stratification of IR.
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Biomarcadores de Tumor/genética , Análisis Citogenético , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Vigilancia de la Población/métodos , Guías de Práctica Clínica como Asunto , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Análisis de SupervivenciaRESUMEN
Myeloid sarcoma in acute myeloid leukemia has been clearly defined by the World Health Organization but studies regarding the prevalence and the prognostic impact of extramedullary acute myeloid leukemia have not been conducted. We performed (18)Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography scans in 10 patients with de novo and relapsed acute myeloid leukemia and histologically proven extramedullary disease. The scans were able to detect the known extramedullary lesions in 9 out of 10 patients (90%). Furthermore, additional extramedullary sites were detected in 6 patients (60%). Thus, it is possible to identify known and clinically undetectable extramedullary manifestations of acute myeloid leukemia. Since most of these patients relapsed within a short period of time after initiation of therapy or had refractory disease, the detection of extramedullary disease with (18)Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography might be helpful in the development of individual treatment algorithms for these high-risk patients.
Asunto(s)
Fluorodesoxiglucosa F18 , Leucemia Mieloide Aguda/diagnóstico por imagen , Imagen Multimodal , Tomografía de Emisión de Positrones , Sarcoma Mieloide/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. PATIENTS AND METHODS: Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m² (I-MAC) or a high-dose of 36 g/m² (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m²) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner. RESULTS: After double induction therapy including intermediate-dose cytarabine (10 g/m²), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups. CONCLUSION: In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m² within first consolidation did not improve treatment outcome.