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1.
Commun Biol ; 4(1): 1184, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645977

RESUMO

Scalable isogenic models of cancer-associated mutations are critical to studying dysregulated gene function. Nonsynonymous mutations of splicing factors, which typically affect one allele, are common in many cancers, but paradoxically confer growth disadvantage to cell lines, making their generation and expansion challenging. Here, we combine AAV-intron trap, CRISPR/Cas9, and inducible Cre-recombinase systems to achieve >90% efficiency to introduce the oncogenic K700E mutation in SF3B1, a splicing factor commonly mutated in multiple cancers. The intron-trap design of AAV vector limits editing to one allele. CRISPR/Cas9-induced double stranded DNA breaks direct homologous recombination to the desired genomic locus. Inducible Cre-recombinase allows for the expansion of cells prior to loxp excision and expression of the mutant allele.  Importantly, AAV or CRISPR/Cas9 alone results in much lower editing efficiency and the edited cells do not expand due to toxicity of SF3B1-K700E. Our approach can be readily adapted to generate scalable isogenic systems where mutant oncogenes confer a growth disadvantage.


Assuntos
Sistemas CRISPR-Cas/fisiologia , Integrases/fisiologia , Íntrons/fisiologia , Neoplasias/fisiopatologia , Quebras de DNA de Cadeia Dupla , Dependovirus , Recombinação Homóloga , Humanos , Neoplasias/enzimologia , Neoplasias/genética
2.
Lancet Haematol ; 7(8): e601-e612, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32563283

RESUMO

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Controle de Infecções/normas , Leucemia/terapia , Transtornos Mieloproliferativos/terapia , Pneumonia Viral/complicações , Guias de Prática Clínica como Assunto/normas , Adulto , COVID-19 , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Gerenciamento Clínico , Prova Pericial , Humanos , Leucemia/virologia , Transtornos Mieloproliferativos/virologia , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Alocação de Recursos , SARS-CoV-2
3.
Front Immunol ; 11: 590494, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33552049

RESUMO

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with immune checkpoint inhibitors (ICIs) are at risk of pneumonitis as well as pneumonia (combined henceforth as ICI-related pulmonary complications). Little is known about the cellular and molecular mechanisms underlying ICI-related pulmonary complications. We characterized lymphocytes from bronchoalveolar lavage (BAL) fluid and peripheral blood from seven AML/MDS patients with pulmonary symptoms after ICI-based therapy (ICI group) and four ICI-naïve AML/MDS patients with extracellular bacterial or fungal pneumonias (controls). BAL T cells in the ICI group were clonally expanded, and BAL IFNγ+ IL-17- CD8+ T and CXCR3+ CCR6+ Th17/Th1 cells were enriched in the ICI group. Our data suggest that these cells may play a critical role in the pathophysiology of ICI-related pulmonary complications. Understanding of these cell populations may also provide predictive and diagnostic biomarkers of ICI-related pulmonary complications, eventually enabling differentiation of pneumonitis from pneumonia in AML/MDS patients receiving ICI-based therapies.


Assuntos
Líquido da Lavagem Broncoalveolar/citologia , Leucemia Mieloide Aguda/imunologia , Síndromes Mielodisplásicas/imunologia , Pneumonia/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunofenotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Pneumonia/induzido quimicamente
4.
Blood Rev ; 40: 100639, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31761380

RESUMO

Most acute myeloid leukemia (AML) patients will be aged more than 65 years. Chronological aging is accompanied by decreasing stem cell and solid organ reserve as well as an increased incidence of medical comorbidity. For the older patient with AML, these patient-specific factors are compounded by an association with complexity of disease biology, chemoresistance, poor tolerance and early mortality with intensive induction therapy. However, the investigation and availability of therapies targeted against various molecular drivers of leukemogenesis, leukemic stem cell persistence, and chemoresistance have provided more options for the patient ineligible for intensive or classical induction therapy, often guided by age >60-65 years by some treatment algorithms. Many providers remain appropriately optimistic that such therapies may overtake the longstanding recommendation for frontline intensive therapy in certain circumstances. Traditional algorithms dichotomizing the optimal treatment modality based on AML patient age are aging themselves and are very likely to soon be outdated.


Assuntos
Envelhecimento , Algoritmos , Fatores Etários , Idoso , Envelhecimento/metabolismo , Envelhecimento/patologia , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade
5.
Blood Rev ; 43: 100650, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31883804

RESUMO

Patients with acute myeloid leukemia (AML) who achieve morphologic remission in the bone marrow after initial treatment often continue to harbor residual leukemic cells that can give rise to disease relapse. Achievement of a deeper remission has been associated with a reduced risk of relapse and improved event-free and overall survival in several studies. However, standardization of diagnostic techniques, sample acquisition and test timing are needed before minimal, also known as measurable, residual disease (MRD) quantification can be used to guide treatment decision making. Furthermore, clinical trial evidence that preemptive intervention at MRD level can alter the natural history of AML is required. Herein, we outline the current landscape of MRD assessment in AML, summarize the available evidence and challenges, and highlight the potential for MRD status to serve as a surrogate endpoint for hard clinical outcomes and as an approvable endpoint in clinical trials for regulatory purposes.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Animais , Gerenciamento Clínico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/genética , Neoplasia Residual/terapia
6.
Clin Infect Dis ; 71(1): 63-71, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31436833

RESUMO

BACKGROUND: The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML). METHODS: 16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion. RESULTS: At the start of IC, higher stool Shannon diversity (hazard ratio [HR], 0.36; 95% confidence interval [CI], .18-.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18-.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum ß-lactamase-producing organism. Patients who received carbapenems for >72 hours had significantly lower α-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73-11.93). CONCLUSIONS: Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.


Assuntos
Microbioma Gastrointestinal , Leucemia Mieloide Aguda , Fezes , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , RNA Ribossômico 16S/genética
8.
Expert Rev Anticancer Ther ; 19(8): 717-729, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31422721

RESUMO

Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells. Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML. Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Adulto , Animais , Benzimidazóis/farmacologia , Proteínas Hedgehog/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Leucemia Mieloide Aguda/patologia , Compostos de Fenilureia/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia
9.
Leuk Lymphoma ; 60(13): 3172-3180, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31125272

RESUMO

Considering the risk of arterio-thrombotic adverse events (AEs), ponatinib trials in previously untreated chronic myeloid leukemia chronic phase (CML-CP) were terminated. We conducted a retrospective CML-CP outcome study of patients who discontinued frontline-ponatinib. Among 51 patients who received frontline ponatinib, 38 discontinued because of FDA request and 13 due to AEs. At ponatinib discontinuation, all patients remained in CP with deepest response being CCyR, n = 7; PCyR, n = 4; MMR, n = 14; MR4.5, n = 26. Of the four patients in PCyR at ponatinib discontinuation, two improved response to CCyR on subsequent TKI. Of seven patients, in CCyR at discontinuation, five improved response to MMR or deeper, one was inevaluable, and another lost response due to treatment noncompliance. With a median follow-up of 39 months, 3-year EFS and OS were 92% and 96%, respectively, indicating favorable long-term outcomes. The cardiac/vascular system AEs with subsequent TKI occurred in patients with prior similar events on ponatinib. AEs occurred up to 9 months post-ponatinib.


Assuntos
Imidazóis/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridazinas/administração & dosagem , Trombose/epidemiologia , Suspensão de Tratamento , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imidazóis/efeitos adversos , Estimativa de Kaplan-Meier , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Estudos Retrospectivos , Trombose/induzido quimicamente , Trombose/prevenção & controle , Adulto Jovem
10.
Best Pract Res Clin Haematol ; 32(1): 74-88, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927978

RESUMO

Autoimmune diseases (ADs) are associated with an increased risk not only of lymphoproliferative disorders but also of myeloid malignancies. The excess risk of myelodysplastic syndromes and/or acute myeloid leukemia is observed across several AD types, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, among others. The risk of developing myeloid neoplasms (MNs) is dependent on several variables, including the specific AD type, chronicity and severity of the AD, type and duration of exposure of disease modifying anti-rheumatic drugs or cytotoxics/immunosuppressives, and genetic predisposition risk. Putative triggering factors linking AD to elevated MN risk include AD-directed medications, shared genetic susceptibilities between the two disease entities, and chronic immune stimulation or bone marrow infiltration by the AD. Molecular mechanisms underpinning leukemogenesis remain largely speculative and warrant further investigation. Leukemias arising in patients with AD are not always 'therapy-related' in that MNs may develop in certain AD subtypes even among patients with no prior therapy exposure. Only a few studies have attempted to determine factors associated with MN development in AD but failed to demonstrate consistent characteristic clinical or paraclinical features. These reports have failed to demonstrate a clear correlation between individual agent exposure and subsequent leukemia development due to the low rates of therapy exposure compounded by the rarity of MN occurrence. Notwithstanding, the leukemogenic potential is best documented with agents such as azathioprine, cyclophosphamide, and mitoxantrone; this risk of MN development does not appear to be shared by biologic approaches such as anti-tumor necrosis factors-alpha inhibitors. In this article, we discuss plausible biologic mechanisms underlying MN pathogenesis in AD and review the data available on the development of MNs in patients with AD.


Assuntos
Artrite Reumatoide , Ciclofosfamida/efeitos adversos , Predisposição Genética para Doença , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda , Lúpus Eritematoso Sistêmico , Mitoxantrona/efeitos adversos , Síndromes Mielodisplásicas , Segunda Neoplasia Primária , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Mitoxantrona/uso terapêutico , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia
11.
Blood Adv ; 3(6): 851-861, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30885996

RESUMO

Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.


Assuntos
Doenças Cardiovasculares/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Trombose/etiologia , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Resultado do Tratamento
12.
Br J Haematol ; 185(2): 219-231, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836448

RESUMO

Evasion of apoptosis has been identified as one of the essential hallmarks of cancer. Inhibitor of apoptosis proteins (IAPs) are implicated in a host of myeloid malignancies, providing the rationale for strategies aimed at neutralizing IAPs to lower the cancer cell apoptosis threshold. Modes of IAP antagonism may include down-regulating IAP expression, up-regulating endogenous pro-apoptotic proteins, such as tumour necrosis factor-α or Fas ligand, or directly antagonizing IAP activity against caspases. Direct targeting of IAPs using mimetics of the second mitochondria-derived activator of caspase (SMAC) protein has shown therapeutic promise by sensitizing the effect of chemotherapy on malignant cells. In pre-clinical studies, SMAC mimetics have demonstrated broad synergistic activity with a wide range of therapeutics, including cytotoxic chemotherapy, receptor tyrosine kinase inhibitors, agents targeting death receptors and alternative mechanisms of cell death, such as necroptosis or autophagy and immune check point blockade. SMAC mimetics represent a novel approach for further investigation in patients with high-risk, chemo-refractory blood cancers, as single agents or in thoughtfully selected combinations. In this review, we discuss the development and therapeutic rationale of small molecule SMAC mimetics, with an emphasis on agents in clinical development for myeloid malignancies.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/agonistas , Leucemia Mieloide/tratamento farmacológico , Proteínas Mitocondriais/agonistas , Síndromes Mielodisplásicas/tratamento farmacológico , Peptidomiméticos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Humanos , Leucemia Mieloide/metabolismo , Terapia de Alvo Molecular/métodos , Síndromes Mielodisplásicas/metabolismo , Peptidomiméticos/farmacologia
13.
Cancer ; 125(11): 1855-1866, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811597

RESUMO

BACKGROUND: Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. METHODS: Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). RESULTS: Testing was performed for 2154 patients, and non-V617F/non-exon 12 JAK2 sequence variants were identified in 114 (5.3%). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3%) in comparison with the MPN (4.6%; P < .001) and AML cohorts (5.2%; P < .001). Detected variants occurred at higher than expected frequencies in patients with MPNs and AML in comparison with the population, and N1108S had a significantly increased prevalence in patients with AML. A JAK2 variant in addition to JAK2 V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P = .003). CONCLUSIONS: Specific JAK2 variants detected in MPNs may be predictors for transformation into AML.


Assuntos
Transformação Celular Neoplásica/genética , Janus Quinase 2/genética , Leucemia Mieloide Aguda/genética , Mutação , Transtornos Mieloproliferativos/genética , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Taxa de Mutação , Prevalência , Análise de Sequência de DNA
14.
Radiographics ; 39(1): 44-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30620703

RESUMO

Leukemias are malignancies in which abnormal white blood cells are produced in the bone marrow, resulting in compromise of normal bone marrow hematopoiesis and subsequent cytopenias. Leukemias are classified as myeloid or lymphoid depending on the type of abnormal cells produced and as acute or chronic according to cellular maturity. The four major types of leukemia are acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Clinical manifestations are due to either bone marrow suppression (anemia, thrombocytopenia, or neutropenia) or leukemic organ infiltration. Imaging manifestations of leukemia in the thorax are myriad. While lymphadenopathy is the most common manifestation of intrathoracic leukemia, leukemia may also involve the lungs, pleura, heart, and bones and soft tissues. Myeloid sarcomas occur in 5%-7% of patients with acute myeloid leukemia and represent masses of myeloid blast cells in an extramedullary location. ©RSNA, 2019.


Assuntos
Leucemia Linfoide/diagnóstico por imagem , Leucemia Mieloide/diagnóstico por imagem , Radiografia Torácica , Tórax/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Leucemia Linfoide/patologia , Leucemia Mieloide/patologia , Masculino , Tomografia por Emissão de Pósitrons , Fatores de Risco , Tomografia Computadorizada por Raios X
16.
Curr Opin Hematol ; 26(2): 77-87, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632987

RESUMO

PURPOSE OF REVIEW: Myelodysplastic syndromes (MDS) are a diverse group of clonal disorders of hematopoietic stem or progenitor cells that represent the most common class of acquired bone marrow failure syndromes in adults. Despite significant improvement in the pathologic insight into this group of disorders, therapeutic options remain limited and allogeneic hematopoietic stem-cell transplantation is the only treatment that can induce long-term remission in patients with MDS. The goals of therapy for MDS are based on disease prognostication, with a focus of minimizing transfusion dependence and preserving quality of life in low-risk groups and preventing progression of disease to acute myeloid leukemia in high-risk groups. Given the dearth of approved treatment options, there is a marked need for novel therapies across the board, and there are several novel agents currently in the pipeline. RECENT FINDINGS: Among the promising agents with preclinical and early phase efficacy in higher risk MDS, apoptosis targeting with BCL-2 inhibitors have been a standout. There is also a keen interest in immunotherapy, and targeted agents (genetic, signaling pathways, bispecific antibodies, antibody-drug conjugates, and others described in this review). SUMMARY: In this review, we will highlight some of the promising new agents currently under investigation for the management of MDS.


Assuntos
Antineoplásicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Humanos
17.
J Clin Pathol ; 72(3): 251-257, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30467242

RESUMO

T-lymphoblastic lymphoma and thymoma are distinct primary mediastinal neoplasms that can have similar clinical presentations and overlapping histological features. Microscopic distinction is occasionally difficult because the immature lymphocytes associated with thymoma may resemble T-lymphoblastic leukaemia/lymphoma cells, morphologically and immunohistochemically. An accurate diagnosis assumes particular importance since the treatment approaches for these two entities differ considerably. Multimodality diagnostic approaches incorporating histological, flow cytometry immunophenotypic' and molecular approaches are required. In this article, we describe four patients, each presenting with a mediastinal tumour in different clinicopathological settings. A detailed report of each case will follow, illustrating the challenges involved in the diagnosis in patients with these mediastinal neoplasms.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Timoma/diagnóstico , Neoplasias do Timo/diagnóstico , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Cancer Discov ; 9(3): 370-383, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30409776

RESUMO

Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Terapia de Salvação , Resultado do Tratamento , Adulto Jovem
19.
Eur J Haematol ; 102(2): 103-110, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30380171

RESUMO

The application of next-generation sequencing (NGS) has enhanced our understanding of the genetic landscape in acquired aplastic anemia (AA). Parallel progress has been in addressing aspects underlying immune dysregulation in disease pathogenesis. Novel insights into the molecular and biologic mechanisms have led to a shift in the paradigm of AA, from a solely autoimmune pathogenic concept toward its recognition as a multifaceted pathophysiology characterized by cytogenetic abnormalities, recurrent somatic mutations, telomere attrition, and immune dysregulation. The detection of recurrent driver mutations disrupting myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)-associated genes has suggested a pathophysiologic link between clonal hematopoiesis in AA and the later development of these clonal disorders. Further, certain AA-related somatic genetic alterations may have clinical implications on treatment response, disease progression, and survival following immunosuppressive therapy. Going forward, wider validation of these genetic abnormalities will allow for their incorporation into a more informative risk stratification system that does not rely solely on clinical factors.


Assuntos
Anemia Aplástica/etiologia , Anemia Aplástica/metabolismo , Anemia Aplástica/sangue , Anemia Aplástica/diagnóstico , Animais , Evolução Clonal/genética , Suscetibilidade a Doenças , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Fenômenos Imunogenéticos , Mutação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
20.
Cancer ; 125(7): 1091-1100, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30521114

RESUMO

BACKGROUND: The revised 2017 European LeukemiaNet (ELN) classification (ELN-2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as the fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN-2017 in comparison with ELN-2010 in younger patients with AML has not been validated to date. METHODS: The authors performed a retrospective study on patients aged <60 years who received idarubicin plus cytarabine (IA)-based induction chemotherapy for newly diagnosed AML. RESULTS: According to ELN-2017 criteria, the number of patients in the favorable (Fav), intermediate (Int), and adverse (Adv) risk categories was 192 patients (27%), 331 patients (46%), and 192 patients (27%), respectively. Overall survival probabilities at 5 years in the Fav, Int, and Adv groups were 57%, 37%, and 18%, respectively. In comparison, the 5-year overall survival probabilities in the Fav (169 patients), intermediate (IR)-1 (80 patients), IR-2 (306 patients), and Adv (160 patients) ELN-2010 categories were 59%, 32%, 40%, and 14%, respectively. Although ELN-2010 historically distinguishes prognosis into IR-1 and IR-2 categories in younger patients, this difference was nullified in the current study cohort. When comparing patients with a low FLT3-ITD AR with those with a high FLT3-ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)-mutated AML (P = .28) or wild-type NPM1 (P = .35), and in those treated with IA alone (P = .79) or those treated with IA and a FLT3 inhibitor (P = .10). CONCLUSIONS: The ELN-2017 more accurately distinguishes prognosis in patients with newly diagnosed AML. The lack of prognostic significance for the FLT3-ITD AR needs further evaluation in different treatment settings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Quimioterapia de Indução , L-Lactato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/genética , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , Contagem de Plaquetas , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
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