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1.
Medicine (Baltimore) ; 99(50): e23615, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327333

RESUMO

RATIONALE: Myeloid sarcomas (MS) are defined as rare extramedullary masses composed of immature myeloid cells. MS mostly develops in patients with acute myeloid leukemia (AML), and involves primarily the skin, soft tissues, bones, and lymph nodes. Pleura and pericardium involvement of MS are extremely uncommon. Polyserositis is also a very rare extramedullary presentation of acute myeloid leukemia (AML). PATIENT CONCERNS: A 30-year-old woman with a complaint of right neck mass combined with coughing for 2 months as well as fever and systemic edema for the last 10 days, was admitted to our center on July 11, 2019. Initial positron emission tomography (PET) scan indicated systemic lymphadenopathy, bilateral pleural effusion, and pericardial effusion. DIAGNOSIS: The initial pathological diagnosis of lymph nodes was MS. Subsequent bone marrow analysis confirmed AML. INTERVENTIONS: Conventional IA induction regimen followed by high-dose cytarabine (HiDAC) regimen. OUTCOMES: Complete absorption of pericardial and pleural effusion after the first cycle of IA induction chemotherapy. LESSONS: Polyserositis can be an extramedullary presentation of AML. Patients with polyserositis should undergo routine flow cytometric analysis. For AML with extamedullary infiltration, systemic chemotherapy should be administered in all confirmed cases.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Sarcoma Mieloide/diagnóstico , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Diagnóstico Diferencial , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Derrame Pericárdico/etiologia , Derrame Pleural/etiologia , Tomografia por Emissão de Pósitrons , Sarcoma Mieloide/complicações , Sarcoma Mieloide/diagnóstico por imagem , Sarcoma Mieloide/tratamento farmacológico , Tomografia Computadorizada por Raios X
2.
J Healthc Eng ; 2020: 6648574, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343851

RESUMO

For the last few years, computer-aided diagnosis (CAD) has been increasing rapidly. Numerous machine learning algorithms have been developed to identify different diseases, e.g., leukemia. Leukemia is a white blood cells- (WBC-) related illness affecting the bone marrow and/or blood. A quick, safe, and accurate early-stage diagnosis of leukemia plays a key role in curing and saving patients' lives. Based on developments, leukemia consists of two primary forms, i.e., acute and chronic leukemia. Each form can be subcategorized as myeloid and lymphoid. There are, therefore, four leukemia subtypes. Various approaches have been developed to identify leukemia with respect to its subtypes. However, in terms of effectiveness, learning process, and performance, these methods require improvements. This study provides an Internet of Medical Things- (IoMT-) based framework to enhance and provide a quick and safe identification of leukemia. In the proposed IoMT system, with the help of cloud computing, clinical gadgets are linked to network resources. The system allows real-time coordination for testing, diagnosis, and treatment of leukemia among patients and healthcare professionals, which may save both time and efforts of patients and clinicians. Moreover, the presented framework is also helpful for resolving the problems of patients with critical condition in pandemics such as COVID-19. The methods used for the identification of leukemia subtypes in the suggested framework are Dense Convolutional Neural Network (DenseNet-121) and Residual Convolutional Neural Network (ResNet-34). Two publicly available datasets for leukemia, i.e., ALL-IDB and ASH image bank, are used in this study. The results demonstrated that the suggested models supersede the other well-known machine learning algorithms used for healthy-versus-leukemia-subtypes identification.


Assuntos
Aprendizado Profundo , Diagnóstico por Computador , Internet das Coisas , Leucemia/classificação , Leucemia/diagnóstico , Reconhecimento Automatizado de Padrão , Algoritmos , Computação em Nuvem , Bases de Dados Factuais , Diagnóstico por Imagem , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Aprendizado de Máquina , Redes Neurais de Computação , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Telemedicina
3.
Ann Hematol ; 99(12): 2911-2925, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33000361

RESUMO

Prior studies have suggested that for leukemia patients with high-risk features, haplo-identical-hematopoietic stem cell transplantation (HID-HSCT) has a stronger anti-leukemia effect compared with HSCT using an identical sibling donor (ISD-HSCT). However, it is unclear whether an HID-HSC transplant also augments the graft-versus-leukemia (GVL) effect among refractory/relapsed (R/R) acute myeloid leukemia (AML) patients who are not in remission (NR). We conducted a retrospective analysis of 124 R/R AML patients with NR status who underwent HID-HSCT between April 2012 and December 2016 and compared these to 27 R/R AML patients who underwent an ISD-HSCT within the same timeframe. Among all of the patients, 68 (45.0%) had primary induction failure (PIF) and 83 (54.9%) were relapsed and had failed to respond to at least one cycle of salvage combination chemotherapy. Myeloablative conditioning regimens were administered to all patients. Here, we present a retrospective multivariate analysis of pre-transplantation risk factors and characteristics of all 151 patients and developed a predictive scoring system to predict patient survival. The median period of follow-up was 46 months for all patients. The HID cohort had a higher 5-year overall survival (OS) compared with the ISD cohort (48.6% ± 4.6% vs 25.9% ± 8.4, respectively; P = 0.017) and higher LFS (leukemia-free survival) (41.6% ± 7.5% vs 25.9% ± 8.4%, respectively; P = 0.019). There was no difference in the 5-year cumulative incidence of non-relapse mortality (NRM) (18.0% ± 3.8% and 34.9% ± 12.6%, respectively; P = 0.212) between the two group. However, the 5-year cumulative incidence of relapse (CIRs) was lower in the HID group compared with the ISD group (55.4% ± 8.9% vs 67.3% ± 9.9%, respectively; P = 0.021). Multivariate analysis showed three risk factors associated with OS and LFS: (1) ISD-HSCT, (2) use of a standardized conditioning regimen, and (3) less than 50% proportional reduction of blast cells in the bone marrow (BM). Based on these three risk factors, we developed a predictive scoring system for R/R AML patients undergoing HSCT. Patients who had a predictive score of 0 and 1 had a 66.6% ± 4.5% and 44.1% ± 3.6% OS rate at 5 years, respectively. Patients with a score ≥ 2 had only a 4.4 ± 0.2% OS rate at 5 years. An HID-HSCT had a better anti-leukemia effect among R/R AML patients with an NR status compared with an ISD-HSCT. We also identified pre-transplantation risk factors to delineate subgroups that could derive maximal benefit from HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Doadores Vivos , Irmãos , Transplante Haploidêntico/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/tendências , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/tendências , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/tendências , Transplante Haploidêntico/tendências , Resultado do Tratamento , Adulto Jovem
4.
J Med Life ; 13(3): 382-387, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072212

RESUMO

By changing the lifestyle and increasing the cancer incidence, accurate diagnosis becomes a significant medical action. Today, DNA microarray is widely used in cancer diagnosis and screening since it is able to measure gene expression levels. Analyzing them by using common statistical methods is not suitable because of the high gene expression data dimensions. So, this study aims to use new techniques to diagnose acute myeloid leukemia. In this study, the leukemia microarray gene data, contenting 22283 genes, was extracted from the Gene Expression Omnibus repository. Initial preprocessing was applied by using a normalization test and principal component analysis in Python. Then DNNs neural network designed and implemented to the data and finally results cross-validated by classifiers. The normalization test was significant (P>0.05) and the results show the PCA gene segregation potential and independence of cancer and healthy cells. The results accuracy for single-layer neural network and DNNs deep learning network with three hidden layers are 63.33 and 96.67, respectively. Using new methods such as deep learning can improve diagnosis accuracy and performance compared to the old methods. It is recommended to use these methods in cancer diagnosis and effective gene selection in various types of cancer.


Assuntos
Aprendizado Profundo , Leucemia Mieloide Aguda/diagnóstico , Humanos , Redes Neurais de Computação , Análise de Componente Principal , Controle de Qualidade
5.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5482-5485, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019220

RESUMO

Acute leukemia often comes with life-threatening prognosis outcome and remains a critical clinical issue today. The implementation of measurable residual disease (MRD) using flow cytometry (FC) is highly effective but the interpretation is time-consuming and suffers from physician idiosyncrasy. Recent machine learning algorithms have been proposed to automatically classify acute leukemia samples with and without MRD to address this clinical need. However, most prior works either validate only on a small data cohort or focus on one specific type of leukemia which lacks generalization. In this work, we propose a transfer learning approach in performing automatic MRD classification that takes advantage of a large scale acute myeloid leukemia (AML) database to facilitate better learning on a small cohort of acute lymphoblastic leukemia (ALL). Specifically, we develop a knowledge-reserved distilled AML pre-trained network with ALL complementary learning to enhance the ALL MRD classification. Our framework achieves 84.5% averaged AUC which shows its transferability across acute leukemia, and our further analysis reveals that younger and elder ALL patient samples benefit more from using the pre-trained AML model.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Idoso , Destilação , Humanos , Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico
6.
Medicine (Baltimore) ; 99(40): e22488, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019444

RESUMO

RATIONALE: Some acute myeloid leukemia (AML) patients present with features mimicking the classical hypergranular subtype of acute promyelocytic leukemia (APL) but without the typical promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement. Herein, we report an AML patient resembling APL but with nucleoporin 98/retinoid acid receptor gamma gene (NUP98/RARG) fusion transcript and Runt-related transcription factor 1 (RUNX1) mutation. PATIENT CONCERNS: An 18-year-old male presented at the hospital with a diagnosis of AML. DIAGNOSES: The patient was diagnosed with bone marrow examination. Bone marrow smear displayed 90.5% promyelocytes. Fluorescence in situ hybridization analysis failed to detect the PML/RARα fusion transcript or RARα amplification. While real-time polymerase chain reaction showed positivity for the NUP98/RARG fusion transcript. G-banding karyotype analysis showed a normal karyotype. INTERVENTIONS: The patient showed resistance to arsenic trioxide and standard 3 + 7 chemotherapy, but eventually achieved complete remission through the Homoharringtonine, Cytarabine, and Aclarubicin chemotherapy. OUTCOMES: These measures resulted in a rapid response and disease control. LESSONS: Acute myeloid leukemia with the NUP98/RARG fusion gene and the RUNX1 mutation may be a special subtype of AML and may benefit from the alkaloid-based regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adolescente , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Diagnóstico Diferencial , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Receptores do Ácido Retinoico/genética
7.
Lancet Haematol ; 7(10): e724-e736, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32896301

RESUMO

BACKGROUND: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups. METHODS: This single centre, phase 2 trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). The study enrolled older patients (aged >60 years) with newly diagnosed AML, not eligible for intensive chemotherapy; secondary AML (progressed after myelodysplastic syndrome or chronic myelomonocytic leukaemia); and relapsed or refractory AML. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less, white blood cell count less than 10 × 109 per L, and adequate end-organ function. Patients with favourable-risk cytogenetics (eg, t[15;17] or core-binding factor AML) or who had received previous BCL2-inhibitor therapy were excluded. Patients received decitabine 20 mg/m2 intravenously for 10 days with oral venetoclax 400 mg daily for induction, followed by decitabine for 5 days with daily venetoclax for consolidation. The primary endpoint was overall response rate. The secondary endpoints analysed within this report include safety, overall survival, and duration of response, in keeping with recommendations of European LeukemiaNet 2017 guidelines. All patients who received at least one dose of treatment were eligible for safety and response assessments. The trial was registered on ClinicalTrials.gov (NCT03404193) and continues to accrue patients. FINDINGS: Between Jan 19, 2018, and Dec 16, 2019, we enrolled 168 patients; 70 (42%) had newly diagnosed AML, 15 (9%) had untreated secondary AML, 28 (17%) had treated secondary AML, and 55 (33%) had relapsed or refractory AML. The median age was 71 years (IQR 65-76) and 30% of patients had ECOG performance status of 2 or higher. The median follow-up for all patients was 16 months (95% CI 12-18; actual follow-up 6·5 months; IQR 3·4-12·4). The overall response rate was 74% (125 of 168 patients; 95% CI 67-80) and in disease subgroups were: 89% in newly diagnosed AML (62 of 70 patients; 79-94), 80% in untreated secondary AML (12 of 15 patients; 55-93), 61% in treated secondary AML (17 of 28 patients; 42-76), and 62% in relapsed or refractory AML (34 of 55 patients; 49-74). The most common treatment-emergent adverse events included infections with grades 3 or 4 neutropenia (n=79, 47%) and febrile neutropenia (n=49, 29%). 139 (83%) of 168 patients had serious adverse events, most frequently neutropenic fever (n=63, 38%), followed by pneumonia (n=17, 10%) and sepsis (n=16, 10%). The 30-day mortality for all patients was 3·6% (n=6, 95% CI 1·7-7·8). The median overall survival was 18·1 months (95% CI 10·0-not reached) in newly diagnosed AML, 7·8 months (2·9-10·7) in untreated secondary AML, 6·0 months (3·4-13·7) in treated secondary AML, and 7·8 months (5·4-13·3) relapsed or refractory AML. The median duration of response was not reached (95% CI 9·0-not reached) in newly diagnosed AML, 5·1 months (95% CI 0·9-not reached) in untreated secondary AML, not reached (95% CI 2·5-not reached) in previously treated secondary AML, and 16·8 months (95% CI 6·6-not reached) in relapsed or refractory AML. INTERPRETATION: Venetoclax with 10-day decitabine has a manageable safety profile and showed high activity in newly diagnosed AML and molecularly defined subsets of relapsed or refractory AML. Future larger and randomised studies are needed to clarify activity in high-risk subsets. FUNDING: US National Institutes of Health and National Cancer Institute.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
8.
Ann Hematol ; 99(12): 2939-2945, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32892274

RESUMO

Sequential protocols combining salvage chemotherapy with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute myeloid leukemia (AML) have been studied more than a decade. Purpose of this retrospective analysis was to evaluate the anti-leukemic efficacy and toxicity of FLAG-IDA protocol (fludarabine, cytarabine, and idarubicin) followed by treosulfan-based conditioning for patients with active AML. From January 2014 to November 2019, a total of 29 active AML patients [median age, 64 years (range, 23-73)] were treated. All patients completed protocol regimen and were transplanted. Five patients (17%) had grade 3-4 toxicities; therefore, treosulfan was substituted with total body irradiation (TBI) non-myeloablative conditioning. Six (20%) patients died within 30 post-transplant days, all from infectious complications. Out of 23 evaluable patients on day 30, 22 (96%) achieved complete hematologic remission with full donor chimerism. Non-relapse mortality (NRM) rates at 1 and 3 years were 22% and 49%, respectively. Median overall survival (OS) was 12 (95% CI, 4-20) months. OS and disease-free survival were 50% and 46% at 1 year and 28% and 17% at 2 years, respectively. Age, gender, disease burden, number of previous lines, and comorbidity score did not predict survival. Sequential strategy combining FLAG-IDA and treosulfan may offer a salvage option for few selected patients with active AML; however, high NRM presents a major obstacle to treatment success. Future efforts should focus on reducing NRM by moderating regimen intensity and by better selection of patients.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bussulfano/análogos & derivados , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Idoso , Bussulfano/administração & dosagem , Estudos de Coortes , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Vidarabina/administração & dosagem , Adulto Jovem
9.
Minerva Med ; 111(5): 386-394, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32955825

RESUMO

Baseline cytogenetic/genetic features have been widely recognized to play a critical prognostic role in acute myeloid leukemia (AML) and have proven useful in designing risk-adapted treatment strategies. Nevertheless, to improve further the outcome of AML patients we are still in need of accurate methods to explore the quality of response and to adequately discriminate patients who are likely to relapse over time from those who are in deep and stable remission. In this view, is it well established that measurement of leukemic cells surviving chemotherapy (called measurable residual disease, MRD) during the course of treatment may be a reliable biomarker in predicting relapse. Detection of MRD relies on highly sensitive techniques, such as quantitative polymerase chain reaction and multiparametric flow cytometry, which, due to their levels of specificity and sensitivity, are increasingly included in the decision-making process of AML treatment. In the present manuscript, we will review the current techniques of MRD investigation and their clinical contribution to AML management.


Assuntos
Citometria de Fluxo/métodos , Leucemia Mieloide Aguda/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Aberrações Cromossômicas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Mutação , Neoplasia Residual , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1/genética , Recidiva , Indução de Remissão , Sensibilidade e Especificidade
10.
Zhonghua Er Ke Za Zhi ; 58(10): 807-812, 2020 Oct 02.
Artigo em Chinês | MEDLINE | ID: mdl-32987459

RESUMO

Objective: To analyze the clinical characteristics and prognosis of mixed phenotype acute leukemia (MPAL) in children. Methods: The data of 29 children diagnosed as MPAL in the Pediatric Blood Disease Center, Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences from January 1, 2005 to December 1, 2019 were collected retrospectively. The morphology, immunophenotypes, cytogenetics, molecular biological characteristics, induction chemotherapy regimen, and prognosis were analyzed. Kaplan-Meier Method was used to draw survival curve. Log-Rank was used for univariate analysis. Results: (1) Among 29 MPAL cases, there were 1 case with KMT2A rearrangement, 1 case with BCR-ABL1, 13 cases with B/myeloid(B-M) type, 12 cases with T/myeloid(T-M) type and 2 cases with acute undifferentiated leukemia. (2) The common immunophenotypes were CD33 (23 cases, 79%), CD34 (25 cases, 86%) and HLA-DR (20 cases, 69%), and CD19 was positive in 17 cases (59%). (3) In molecular genetics analysis, 8 cases were detected to have abnormal gene fusion, including 1 case with MLL-AF4 fusion gene, 1 case with BCR-ABL1 fusion gene, 3 cases with TEL-AML1 fusion gene, 2 cases with WT1 and 1 case with FLT3-ITD. (4) In cytogenetics analysis, 27 cases obtained chromosome karyotypes, including 14 cases with abnormal karyotypes and 10 cases were complex karyotypes. (5) In treatment efficacy analysis, 27 cases received induction chemotherapy and the complete remission(CR) rate was 85%(23/27).The 5-year disease free survival(DFS) rate was (71±10)% and 5-year overall survival(OS) rate was (74±10)%. Thirteen of 14 cases received acute lymphoblastic leukemia(ALL) induction therapy achieved CR, while 10 of 12 cases received hybrid induction therapy achieved CR. No significant difference was found in 5 year-OS rates between cases with ALL induction therapy and hybrid induction therapy ((77±15)% vs. (80±13)%, χ²=0.027,P=0.870). Conclusions: MPAL is a rare childhood leukemia and is prone to incorporate complex karyotypes. Induction therapy with ALL or hybrid regimens is a good choice to obtain favorable prognosis.


Assuntos
Leucemia Mieloide Aguda , Doença Aguda , Criança , Humanos , Leucemia Mieloide Aguda/diagnóstico , Fenótipo , Prognóstico , Estudos Retrospectivos
12.
Am J Hematol ; 95(11): 1399-1420, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32744763

RESUMO

DISEASE OVERVIEW: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). Myelodysplastic syndromes occur more frequently in older males and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry and molecular genetics is usually complementary and may help refine diagnosis. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly accepted system is the Revised International Prognostic Scoring System (IPSS-R). Somatic mutations can help define prognosis and therapy. RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential for allogeneic stem cell transplantation (alloSCT) and prior exposure to hypomethylating agents (HMA). Goals of therapy are different in lower-risk patients than in higher-risk individuals and in those with HMA failure. In lower-risk MDS, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher-risk disease, the goal is to prolong survival. In 2020, we witnessed an explosion of new agents and investigational approaches. Current available therapies include growth factor support, lenalidomide, HMAs, intensive chemotherapy and alloSCT. Novel therapeutics approved in 2020 are luspatercept and the oral HMA ASTX727. At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after HMA-based therapy. Options include participation in a clinical trial, cytarabine-based therapy or alloSCT.


Assuntos
Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transplante de Células-Tronco , Administração Oral , Aloenxertos , Intervalo Livre de Doença , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Medição de Risco , Taxa de Sobrevida
14.
Leukemia ; 34(11): 2903-2913, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32733012

RESUMO

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Terapia de Alvo Molecular , Mutação , Adulto , Idoso , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Medula Óssea/patologia , Análise Mutacional de DNA , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
15.
Exp Hematol ; 89: 80-86, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32739457

RESUMO

In the elderly with cytopenia, the diagnosis of myelodysplastic syndrome (MDS) may be missed. Cytokine levels contribute to the pathology of MDS. Hence, the objectives were to evaluate cytogenetic profile as a prognostic indicator in risk stratification and cytokine levels as a screening tool in patients with cytopenia for diagnosis. Over 2 years (2016-2018), 150 elderly patients were screened. MDS diagnosis was confirmed by morphology. Interleukin-2 (IL-2) and IL-6 levels were assessed in 50 patients, and karyotyping was performed in 20 confirmed cases of MDS. Age-matched healthy controls were used for comparison of cytokine levels. Among 150 patients, 88.6% had anemia, including nutritional anemia (51.2%). MDS diagnosis was confirmed in 35 patients. In 15 patients, unexplained cytopenia (UC) was present. Karyotyping in 20 MDS patients was normal in 15 (75%) patients and revealed a complex karyotype in four (20%) patients and double chromosomal abnormality in one (5%) patient. The Revised International Prognostic Scoring System (IPSS-R) scored 91% in the low-risk group and 9% (n = 3) in the high-risk group; the latter three developed acute myeloid leukemia (AML) and two of them had a 7q deletion. Among the 15 cases of UC, one patient died from refractory anemia. No significant difference in levels of IL-2 and IL-6 were found between MDS and UC patients when compared with healthy controls, as well as between different risk groups and karyotypes. A significant difference in IL-2 levels was found in MDS patients with disease progression and with stable disease. On the basis of the findings, it is suggested that IL-2 levels will help in predicting disease progression.


Assuntos
Anemia/genética , Biomarcadores Tumorais/genética , Interleucina-2/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Síndrome de Williams/genética , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/diagnóstico , Anemia/patologia , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Estudos Transversais , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Interleucina-2/sangue , Interleucina-6/sangue , Interleucina-6/genética , Cariótipo , Cariotipagem , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Síndrome de Williams/sangue , Síndrome de Williams/diagnóstico , Síndrome de Williams/patologia
16.
Ann Hematol ; 99(10): 2417-2427, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862286

RESUMO

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/terapia , Proteínas de Neoplasias/genética , Transplante de Células-Tronco de Sangue Periférico , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/química , Terapia Combinada , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Reação em Cadeia da Polimerase/métodos , Prognóstico , Proteínas Proto-Oncogênicas c-abl/genética , Transativadores/biossíntese , Resultado do Tratamento , Proteínas Supressoras de Tumor/biossíntese , Adulto Jovem
17.
Ann Hematol ; 99(9): 2173-2180, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621177

RESUMO

Resistant disease is still a main obstacle in acute myeloid leukemia (AML) treatment. Therefore, individual genetic variations affecting therapy response are gaining increasing importance. Both SNPs and ABC transporter genes could already be associated with drug resistance. Here, we report allelic variants of MRP1 (ABCC1) SNPs rs129081, rs212090, and rs212091 with significant influences on survival in AML patients. DNA was extracted from bone marrow samples (n = 160) at diagnosis. Genotyping 48 SNPs within seven different ABC transporter genes using real-time PCR revealed rs129081 GG variant with a significant higher OS (p = 0.035) and DFS (p = 0.01). Comparing TT and AA rs212090 variants showed significant influences on DFS (p = 0.021). SNP rs212091 GG expression was associated with worse OS (p = 0.006) and a significant difference in DFS between alleles GG and AA (p = 0.018). The multivariable models confirmed a significant influence on OS for rs212091 (AA HR = 0.296, 95% CI 0.113-0.774, p = 0.013 and GG p = 0.044). Rs129081 variant CG, TT of rs212090, AA, and AG of rs212091 demonstrated significant impact on DFS (p = 0.024, p = 0.029, p = 0.017, and p = 0.042, respectively). This analysis demonstrates a significant influence of MRP1 SNPs on survival in AML. As they were not associated to prognostic characteristics, we suggest these SNPs to be independent prognostic markers for AML.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Taxa de Sobrevida/tendências , Adulto Jovem
18.
Sci Rep ; 10(1): 12152, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699322

RESUMO

The mutational spectrum and prognostic factors of NRAS-mutated (NRASmut) acute myeloid leukemia (AML) are largely unknown. We performed next-generation sequencing (NGS) in 1,149 cases of de novo AML and discovered 152 NRASmut AML (13%). Of the 152 NRASmut AML, 89% had at least one companion mutated gene. DNA methylation-related genes confer up to 62% incidence. TET2 had the highest mutation frequency (51%), followed by ASXL1 (17%), NPM1 (14%), CEBPA (13%), DNMT3A (13%), FLT3-ITD (11%), KIT (11%), IDH2 (9%), RUNX1 (8%), U2AF1 (7%) and SF3B1(5%). Multivariate analysis suggested that age ≥ 60 years and mutations in U2AF1 were independent factors related to failure to achieve complete remission after induction therapy. Age ≥ 60 years, non-M3 types and U2AF1 mutations were independent prognostic factors for poor overall survival. Age ≥ 60 years, non-M3 types and higher risk group were independent prognostic factors for poor event-free survival (EFS) while allogenic hematopoietic stem cell transplantation was an independent prognostic factor for good EFS. Our study provided new insights into the mutational spectrum and prognostic factors of NRASmut AML.


Assuntos
GTP Fosfo-Hidrolases/genética , Leucemia Mieloide Aguda/diagnóstico , Proteínas de Membrana/genética , Adolescente , Adulto , Idoso , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Razão de Chances , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Risco , Fator de Processamento U2AF/genética , Adulto Jovem
19.
Medicine (Baltimore) ; 99(27): e21119, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629746

RESUMO

INTRODUCTION: Myeloid sarcoma (MS) is a rare tumor mass. It may occur at any extramedullary anatomic sites but is uncommon in the sinonasal location.MS commonly presents concurrently with acute myeloid leukemia (AML), but it may predate AML over several months or years, named isolated MS. PATIENT CONCERNS: We report a case of a 15-month-old child who presented with mouth breathing, bilateral rhinorrhea, palpebral edema and proptosis. The routine blood tests were normal for the first few months. Computed tomography scan revealed neoplasm in nasal cavity. DIAGNOSIS: The patient was definitely diagnosed with isolated MS in the nasal cavity through immunohistochemistry combined with clinical features and radiological investigations, and MS further progressed to AML which was confirmed by hematologist. INTERVENTIONS: Endoscopic sinus surgery was performed to acquire specimens. After diagnosis, the patient was promptly treated with systemic chemotherapy. OUTCOMES: All symptoms gradually subsided and the mass of nasal cavity was invisible. No relapse occurred during follow-up. CONCLUSION: Sinonasal MS may be misdiagnosed and should be considered when symptoms persist and worsen. Prompt clinic examinations are essential for cases with suspected MS. Diagnosis of MS is dependent on the immunohistological investigations combined with clinical features, radiological investigations. Early diagnosis and systemic chemotherapy are vital for patients to achieve best prognosis.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Cavidade Nasal/diagnóstico por imagem , Sarcoma Mieloide/complicações , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Erros de Diagnóstico/prevenção & controle , Diagnóstico Precoce , Edema/etiologia , Exoftalmia/etiologia , Doenças Palpebrais/patologia , Humanos , Imuno-Histoquímica/métodos , Lactente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/cirurgia , Masculino , Cavidade Nasal/patologia , Cavidade Nasal/cirurgia , Sarcoma Mieloide/diagnóstico por imagem , Sarcoma Mieloide/metabolismo , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
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