RESUMO
In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2-6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5-39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation (n = 1 DNMT3A, n = 1 IDH2, n = 1 TET2). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.
Assuntos
Síndromes Mielodisplásicas , Neoplasias , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Células Clonais/patologia , Medula Óssea/patologia , Apoptose , MutaçãoRESUMO
Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Leucemia Mielomonocítica Juvenil , Mutação , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Masculino , Feminino , Lactente , Pré-Escolar , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Criança , Transdução de Sinais , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Nitrilas , PirimidinasRESUMO
Central venous catheters (CVC) placed either via the internal jugular vein (IJV) or the subclavian vein (SCV) are routinely used in patients with hematologic malignancies. In this retrospective study, we systematically compared CVC-associated complications for both insertion sites, IJV and SCV. Between January 2011 and June 2013, all consecutive patients (n = 87) were included with at least one CVC (n = 153; n = 94 IJV; n = 59 SCV) at our institution due to induction/consolidation for AML/ALL or autologous hematopoietic cell transplantation (HCT). Primary study endpoints were central line-associated (CLABSI), catheter-related (CRBSI) blood stream infections and local inflammation (LI) at the insertion site. CRBSI occurred earlier and more frequently in the IJV- versus the SCV-group with an incidence rate of CRBSI at day 15 of 10% versus 0% (p = .04) and a rate of CRBSI per 1000 CVC days of 5.7 versus 1.2. In addition, CLABSI was detected more often in IJV- compared to SCV-CVC (26% vs. 8%, p = .009). Conversely, LI occurred more frequently and earlier in SCV- versus IJV-CVC (88% vs. 56%, p < .0001) with a median time to LI of 9 versus 14 days (p < .0001). The strongest risk factor for the endpoints CRBSI, CLABSI, and LI was the insertion site. However, SCV insertion was a risk factor for LI (p = .001, HR: 2.0), insertion in the IJV a risk factor for CLABSI (p = .044, HR: 2.7) and CRBSI (p = .036, HR: 5.4). These results demonstrate a differential effect of the insertion site of CVC in neutropenic patients with a significantly reduced frequency of CVC-related blood stream infections in SCV-CVC.
Assuntos
Infecções Relacionadas a Cateter/epidemiologia , Cateterismo Venoso Central/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Neoplasias Hematológicas/terapia , Adulto , Idoso , Infecções Relacionadas a Cateter/etiologia , Feminino , Neoplasias Hematológicas/epidemiologia , Humanos , Incidência , Inflamação/epidemiologia , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Patient-derived xenograft (PDX) models have emerged as versatile preclinical platforms for investigation of functional pathomechanisms in myelodysplastic syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized three-dimensional scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been found to enable improved engraftment rates of healthy and malignant human hematopoiesis. We therefore interrogated the feasibility of using four different three-dimensional ossicle-based PDX models for application with primary MDS samples. In a fully standardized comparison, we evaluated scaffold materials such as Gelfoam, extracellular matrix (ECM), and human or xenogenous bone substance in comparison to intrafemoral (IF) co-injection of bone marrow (BM)-derived mesenchymal stromal cells (MSCs) and CD34+ hematopoietic stem and progenitor cells (HSPCs). Our study included13 primary MDS patient samples transplanted in parallel according to these five different conditions. Engraftment of MDS samples was assessed by flow cytometry, immunohistological staining, and molecular validation. We determined that three-dimensional ossicle-based methods achieved higher relative rates of engraftment and enabled long-term retrievability of patient-derived MSCs from implanted ossicles. In summary, HSPCs and MSCs derived from MDS BM, which did not significantly engraft in NSG mice after intrafemoral injection, were able to colonize humanized scaffold models. Therefore, these models are promising new xenotransplantation techniques for addressing preclinical and functional questions of the interaction between hematopoiesis and the BM niche in MDS.
Assuntos
Células-Tronco Mesenquimais , Síndromes Mielodisplásicas , Animais , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Hematopoese , Células-Tronco Hematopoéticas/patologia , Humanos , Células-Tronco Mesenquimais/patologia , Camundongos , Síndromes Mielodisplásicas/patologia , Transplante HeterólogoRESUMO
Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
Assuntos
Leucemia Mielomonocítica Juvenil , Adulto , Criança , Humanos , Leucemia Mielomonocítica Juvenil/genética , Mutação , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-cbl/genéticaRESUMO
Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.
Assuntos
Antineoplásicos/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Lenalidomida/farmacologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
CONTEXT: Prediction of AH is frequently undertaken in the clinical setting. The commonly used methods are based on the assessment of skeletal maturation. Predictive algorithms generated by machine learning, which can already automatically drive cars and recognize spoken language, are the keys to unlocking data that can precisely inform the pediatrician for real-time decision making. OBJECTIVE: To use machine learning (ML) to predict adult height (AH) based on growth measurements until age 6 years. METHODS: Growth data from 1596 subjects (798 boys) aged 0-20 years from the longitudinal GrowUp 1974 Gothenburg cohort were utilized to train multiple ML regressors. Of these, 100 were used for model comparison, the rest was used for 5-fold cross-validation. The winning model, random forest (RF), was first validated on 684 additional subjects from the 1974 cohort. It was additionally validated using 1890 subjects from the GrowUp 1990 Gothenburg cohort and 145 subjects from the Edinburgh Longitudinal Growth Study cohort. RESULTS: RF with 51 regression trees produced the most accurate predictions. The best predicting features were sex and height at age 3.4-6.0 years. Observed and predicted AHs were 173.9â ±â 8.9 cm and 173.9â ±â 7.7 cm, respectively, with prediction average error of -0.4â ±â 4.0 cm. Validation of prediction for 684 GrowUp 1974 children showed prediction accuracy râ =â 0.87 between predicted and observed AH (R2 = 0.75). When validated on the 1990 Gothenburg and Edinburgh cohorts (completely unseen by the learned RF model), the prediction accuracy was râ =â 0.88 in both cases (R2 = 0.77). AH in short children was overpredicted and AH in tall children was underpredicted. Prediction absolute error correlated negatively with AH (Pâ <â .0001). CONCLUSION: We show successful, validated ML of AH using growth measurements before age 6 years. The most important features for prediction were sex, and height at age 3.4-6.0. Prediction errors result in over- or underestimates of AH for short and tall subjects, respectively. Prediction by ML can be generalized to other cohorts.
Assuntos
Antropometria/métodos , Estatura , Aprendizado de Máquina , Adulto , Algoritmos , Criança , Pré-Escolar , Técnicas de Apoio para a Decisão , Gráficos de Crescimento , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pediatria , Valor Preditivo dos Testes , Análise de RegressãoRESUMO
Although acute promyelocytic leukemia (APL) has evolved to the AML entity with the best prognosis, typical 'early death' (ED) events still account for mortality rates of â¼20% in population-based studies. To investigate this poorly understood issue we performed whole transcriptome analysis of n = 7 APL ED cases compared to n = 7 APL cases with long term remission. We discovered the proteins S100A8/S100A9 and EFEMP1 as the most differentially expressed factors. In an independent cohort of n = 58 APL patients EFEMP1 over-expression was associated with a worse overall survival. Furthermore, a subgroup analysis of ED caused by hemorrhagic complications revealed an association of metallothioneins (MT1G/MT1E) with higher bleeding rates, ED events and negative prognostic effects on overall survival. Finally, we identified a novel TPM4-KLF2 fusion transcripts in 44/64 APL samples. In summary, we report a comprehensive transcriptomic analysis and novel potential biomarkers of ED biology, which highlight novel pathways in ED events in APL.
Assuntos
Leucemia Promielocítica Aguda , Sequência de Bases , Biomarcadores , Proteínas da Matriz Extracelular , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Prognóstico , RNAAssuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Leucemia Mielomonocítica Juvenil/genética , Proteínas dos Microfilamentos/genética , Sorafenibe/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Linhagem Celular , Humanos , Lactente , Masculino , Camundongos , Mutação/genética , Análise de Sequência de RNA/métodos , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT. PROCEDURE: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing. RESULTS: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high-intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. CONCLUSIONS: Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Genes Neoplásicos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Terapia Neoadjuvante , Análise de Sequência de DNA , Carga Tumoral/efeitos dos fármacos , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , DNA de Neoplasias/sangue , Avaliação de Medicamentos , Monitoramento de Medicamentos , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/sangue , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Proteínas de Neoplasias/genética , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Esplenectomia , Condicionamento Pré-TransplanteRESUMO
OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Análise Citogenética , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Recidiva , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
INTRODUCTION: Although treatment of acute promyelocytic leukemia (APL) has evolved dramatically during the past decades, especially with the introduction of all-trans retinoic acid, risk stratification remains an important issue. To date, relapse risk can be predicted by leukocyte and platelet counts only. In the present report, we present a validation study on 3 candidate genes and a newly developed molecular risk score for APL in 2 independent patient cohorts. PATIENTS AND METHODS: An integrative risk score combining the expression levels of BAALC, ERG, and WT1 was calculated for 79 de novo APL patients from the original cohort and 76 de novo APL patients from a validation cohort. Gene expression analysis was executed the same for both cohorts, and the results regarding the effect on patient outcomes were compared. RESULTS: The expression levels of BAALC, ERG, and WT1 were similar in both cohorts compared with the healthy controls. The relapse and survival rates were not different between the low- and high-risk patients according to the Sanz score. However, application of the molecular risk score on the validation cohort distinctly discriminated patients according to their risk of relapse and death just as in the original APL cohort, although single gene analyses could not reproduce the negative prognostic impact. CONCLUSION: The analysis clearly validated the prognostic effect of the integrative risk score on the outcome in APL patients. The value was further empowered because the single gene analyses did not show similar results. Whether the integrative risk score retains its prognostic power in the chemotherapy-free setting should be investigated further.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Regulador Transcricional ERG/genética , Proteínas WT1/genética , Adulto JovemRESUMO
History, examinations and diagnosis A young patient consulted the hospital because of spontaneous hematomas. The combination of pancytopenia and coagulopathy in the blood and the proving cytogenetic and moleculargenetic examinations of the bone marrow lead to the diagnosis of low-risk acute promyelocytic leukemia (APL). Therapy and clinical course During the combination therapy with ATRA and ATO, the patient developed a severe differentiation syndrome and hyperleukocytosis. Management of the condition was only possible due to clinical expertise and massive substitution of blood products and clotting factors. Conclusion The case illustrates the difficulty and dangers of APL induction therapy even with a favorable initial clinical presentation despite the generally low toxicity of new therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dispneia/induzido quimicamente , Febre/induzido quimicamente , Hipotensão/induzido quimicamente , Leucemia Promielocítica Aguda/tratamento farmacológico , Pneumopatias/induzido quimicamente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Arsenicais/efeitos adversos , Diagnóstico Diferencial , Dispneia/diagnóstico , Dispneia/prevenção & controle , Feminino , Febre/diagnóstico , Febre/prevenção & controle , Humanos , Hipotensão/diagnóstico , Hipotensão/prevenção & controle , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/diagnóstico , Leucocitose/induzido quimicamente , Leucocitose/diagnóstico , Leucocitose/prevenção & controle , Pneumopatias/diagnóstico , Pneumopatias/prevenção & controle , Óxidos/administração & dosagem , Óxidos/efeitos adversos , Fatores de Risco , Índice de Gravidade de Doença , Síndrome , Resultado do Tratamento , Tretinoína/administração & dosagem , Tretinoína/efeitos adversosRESUMO
To date risk stratification in acute promyelocytic leukemia (APL) is based on highly dynamic leukocyte and platelet counts only. To identify a more robust risk stratification model, a molecular risk score was developed based on expression levels of the genes BAALC, ERG and WT1. Hereby, the main focus was on prediction of relapse. The integrative risk score divided patients into two groups with highly significant differences in outcome. It discriminated a high risk group with a high incidence of relapse successfully from a low risk group with no APL-related events after achievement of first remission. Especially the concurrent presence of molecular risk factors showed to be a negative prognostic factor in APL. The molecular risk score might be a promising approach to guide monitoring of APL patients and therapeutic decisions in the future.
RESUMO
Wilms' tumor 1 gene (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking. WT1 expression was analyzed in bone marrow samples of 79 patients with APL at initial diagnosis. Patients had a differing outcome according to their level of WT1 expression. In patients who achieved a complete remission (CR), low or high WT1 expression was significantly associated with inferior overall survival (OS) compared to intermediate WT1 expression (49% for WT1high vs. 63% for WT1low vs. 93% for WT1int; p=0.008). Moreover, there were significant differences in relapse-free survival (RFS) between the three expression groups (42% for WT1high vs. 63% for WT1low vs. 83% for WT1int; p=0.047). In multivariable analysis WT1 expression showed an independent prognostic impact on OS of responders to induction therapy. In conclusion, the level of WT1 expression can add prognostic information in APL risk stratification.
Assuntos
Expressão Gênica , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Proteínas WT1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Biópsia , Medula Óssea/patologia , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Indução de Remissão , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
We evaluated the prognostic value of BAALC expression in 86 patients with acute promyelocytic leukemia (APL). At 10 years, the overall survival (OS) was 66% in all patients and 75% in patients who achieved a complete remission (CR). Patients in the BAALC(low) group showed an OS of 87% as compared to 60% in the BAALC(high) group (p=0.019). This difference was more pronounced in treatment responders (92% vs. 70%; p=0.035). In multivariate analyses low BAALC expression retained its prognostic relevance. In conclusion, BAALC expression analysis might be useful in further risk stratification in APL patients.
Assuntos
Expressão Gênica , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Recidiva , Sobrevida , Adulto , Idoso , Sequência de Bases , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens.
Assuntos
Biomarcadores Tumorais/genética , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Transativadores/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Regulador Transcricional ERG , Regulação para Cima/genética , Adulto JovemRESUMO
To search for new copy number alterations (CNAs) in acute promyelocytic leukemia (APL), we analyzed DNA from leukemic blasts of 93 acute promyelocytic leukemia (APL) patients with Genome-Wide SNP 6.0 arrays (SNP-A). We identified 259 CNAs consisting of 170 heterozygous deletions, 82 amplifications, and 7 regions of copy number neutral loss of heterozygosity. One of the most common CNAs was a deletion on chromosomal subband 1q31.3 in 13 of 93 (14%) patients encompassing the coding regions for the microRNAs mir181a1/b1. In multivariable analysis with the covariates age, white blood cell count, platelet count, and FLT3-ITD/FLT3 D835 mutations we found that after adjustment for patients' age (P<0.0001), patients with 2 or more CNAs detected by SNP-A had a higher risk of death (hazard ratio=5.942, P=0.0015) than patients with 0 or 1 CNA. Deletions of 1q31.3 were associated with a higher number of CNAs (median 2 vs. 8, P<0.0001) and were a strong independent prognostic factor for an increased risk of relapse (hazard ratio=28.9, P=0.0031). This study presents a comprehensive assessment of new CNAs as pathomechanistically relevant targets and possible prognostic factors which could refine risk stratification of APL.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Deleção de Genes , Leucemia Promielocítica Aguda/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Variações do Número de Cópias de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Fatores de Risco , Estatísticas não Paramétricas , Translocação GenéticaRESUMO
HISTORY AND CLINICAL FINDINGS: A 24-year-old HIV-positive patient was admitted to hospital on account of increasing headache. INVESTIGATIONS: On admission, a patient with severe headache, nausea and vomiting but without neurologic deficiencies was seen. The diagnosis of a cryptococcal meningoencephalitis could be confirmed by direct detection of cryptococci in the liquor. TREATMENT AND COURSE: The patient was treated with a combination of fluconazole, flucytosine and amphotericin B, and an antiretroviral therapy (ART) was started on account of the severe immunodeficiency. The patient improved during the following weeks, and fluconazole was administered as maintainance therapy. About 2 months later, the patient presented again with severe headache. On lumbar puncture, a great amount of cryptococci could be detected, and the antimycotic combination therapy was restarted. An antimycotic testing of the cryptococci revealed a partial resistance to fluconazole. Therefore, fluconazole was replaced by voriconazole which has been continued ever since. Cryptococci could not be detected on further investigations of the liquor. The patient's condition worsened again 8 months after initiation of the ART. MR scan showed a slight cerebral edema. There was no hint of an opportunistic infection nor of a lymphoma. The complaints were supposed to be due to an immune restoration inflammatory syndrome (IRIS), and administration of high steroid dosages was started. The complaints resolved within 48 h, and the patient's condition has been stable ever since (19 months). CONCLUSION: Cryptococcal meningoencephalitis is an opportunistic infection in AIDS. Therapeutically, various regimens containing two to three different antimycotic drugs show good efficacy but resistance to antimycotics has to be considered. As in other HIV associated infections, an IRIS has to be taken into account.