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1.
Br J Haematol ; 195(3): 378-387, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34340254

RESUMO

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos/uso terapêutico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antimetabólitos/efeitos adversos , Antimetabólitos/farmacologia , Artralgia/induzido quimicamente , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Constipação Intestinal/induzido quimicamente , Metilação de DNA/efeitos dos fármacos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Risco
4.
Leuk Res ; 101: 106511, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33517186

RESUMO

Chronic myelomonocytic leukemia (CMML) is characterized by myelomonocytic bias and monocytic proliferation. Whether cell-intrinsic innate immune or inflammatory upregulation mediate disease pathogenesis and phenotype or whether the degree of aberrant monocytic differentiation influences outcomes remains unclear. We compared the transcriptomic features of bone marrow CD34+ cells from 19 patients with CMML and compared to healthy individuals. A total of 1495 genes had significantly differential expression in CMML (q<0.05, fold change>2), including 1271 genes that were significantly upregulated and 224 that were significantly downregulated in CMML. Top upregulated genes were associated with interferon (IFN) alpha and beta signaling, chemokine receptors, IFN gamma, G protein-coupled receptor ligand signaling, and genes involved in immunomodulatory interactions between lymphoid and non-lymphoid cells. Additionally, 6 gene sets were differentially upregulated and 139 were significantly downregulated in patients with myeloproliferative compared to myelodysplastic CMML. A total of 23 genes involved in regulation of monopoiesis were upregulated in CMML compared to healthy controls. We developed a prediction model using Cox regression including 3 of these genes, which differentiated patients into two prognostic subsets with distinct survival outcomes. This data warrants further evaluation of the roles and therapeutic potential of type I IFN signaling and monopoiesis in CMML.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon Tipo I/administração & dosagem , Leucemia Mielomonocítica Crônica , Mielopoese/efeitos dos fármacos , Proteínas de Neoplasias , Regulação para Cima/efeitos dos fármacos , Feminino , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética
6.
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
7.
Blood Adv ; 4(3): 482-495, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32027746

RESUMO

TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors.


Assuntos
Síndromes Mielodisplásicas , Proteína Supressora de Tumor p53 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Frequência do Gene , Genômica , Humanos , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Prognóstico , Proteína Supressora de Tumor p53/genética , Adulto Jovem
8.
Leuk Lymphoma ; 61(6): 1493-1499, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32036728

RESUMO

LILRB4 is expressed in AML M4/M5 cells and negatively regulates immune cell activation via T-cell suppression. Its expression and role in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS) are unknown. We investigated LILRB4 expression in 19 CMML and 27 MDS patients and correlated it with response to subsequent hypomethylating agent (HMA) therapy. LILRB4 RNA expression was increased in CMML patients when compared to MDS patients and healthy controls (q < 0.1) and slightly increased in patients who responded to HMAs (q > 0.1). Pathway analysis revealed upregulation of PD-1 signaling, CTLA-4 signaling, and inflammatory response, and gene correlates were positively associated with CTLA-4 expression. Given current modest results with immunotherapy in myeloid malignancies, further investigation of LILRB4 as an immune checkpoint inhibitor target is needed. With the positive correlation between LILRB4 and CTLA-4 expression, combining anti-LILRB4 and anti-CTLA-4 agents may be a novel therapeutic approach in myeloid malignancies that warrants larger studies.


Assuntos
Leucemia Mielomonocítica Crônica , Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicas , Humanos , Imunoterapia , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/genética , Glicoproteínas de Membrana , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Receptores Imunológicos/genética , Regulação para Cima
9.
Hematol Oncol ; 37(1): 96-102, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30153704

RESUMO

Trabectedin is an FDA-approved DNA minor groove binder that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia-free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients.


Assuntos
Antineoplásicos/efeitos adversos , Carbolinas/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Carbolinas/administração & dosagem , Carbolinas/uso terapêutico , Aberrações Cromossômicas , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Resultado do Tratamento , Adulto Jovem
10.
Acad Med ; 91(9): 1205-10, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27415444

RESUMO

Attention to the health and wellness of postgraduate medical trainees has increased considerably in recent years, yet the scholarly literature consistently indicates that, in many instances, the medical and mental health care needs of this population remain unmet or only partially met. As a result, trainee health care often falls short of the current standards of the medical profession. Combined with the prevalence of burnout and other mental health conditions among trainees, inadequate health care for this patient population may result in significant negative consequences for trainees' health, safety, and performance.Here, the authors review the scholarly literature explicating the health care needs of postgraduate trainees. They explore the patient-centered medical home model as a potentially effective solution to address the unmet and partially met health care needs of trainees. The authors describe several practical interventions to improve access to care. These include care coordination and referral support, confidential care without perceived conflicts of interest in the training environment, co-location of medical and mental health care, and accommodations for schedule constraints. Finally, the authors explore the role of the medical home in developing and supporting broader institutional efforts to promote wellness.


Assuntos
Acesso aos Serviços de Saúde/organização & administração , Internato e Residência/métodos , Determinação de Necessidades de Cuidados de Saúde/organização & administração , Assistência Centrada no Paciente/métodos , Pacientes/psicologia , Médicos/psicologia , Estresse Psicológico/prevenção & controle , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente
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