RESUMO
Obinutuzumab (GA101) is a humanized anti-CD20 monoclonal antibody used in the treatment of B-cell malignancies. Under rare occasions, obinutuzumab may induce acute and severe thrombocytopenia. However, little is known about this side effect, referred to as "obinutuzumab-induced acute thrombocytopenia" (OIAT). Here, we report 2 cases of OIAT and review the literature to inform the management and outcome of this rare but life-threatening complication. The first case is a 74 year- old woman who was treated with obinutuzumab-Cyclophosphamide, Vincristine, Prednisone (CVP) for a previously untreated follicular lymphoma. This patient experienced an acute thrombocytopenia with a drop in her platelet count from 376 G/L to 3 G/L the day after treatment. The second case is a 44 year- old woman who was treated with obinutuzumab as a pre-treatment dose (day-8) before glofitamab infusion as a 4th line therapy for mantle cell lymphoma. This patient experienced an acute thrombocytopenia with a drop in her platelet count from 76 G/L (due to splenomegaly and bone marrow involvement) to 3 G/L the day after treatment. OIAT is a rare but life-threatening complication. Physicians should be aware of this adverse event to optimally detect and treat this complication.
Assuntos
Antineoplásicos , Trombocitopenia , Humanos , Feminino , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antineoplásicos/uso terapêutico , Trombocitopenia/etiologiaRESUMO
Complementary tools are warranted to increase the sensitivity of the initial testing for COVID-19. We identified a specific 'sandglass' aspect on the white blood cell scattergram of COVID-19 patients reflecting the presence of circulating plasmacytoid lymphocytes. Patients were dichotomized as COVID-19-positive or -negative based on reverse transcriptase polymerase chain reaction (RT-PCR) and chest computed tomography (CT) scan results. Sensitivity and specificity of the 'sandglass' aspect were 85·9% and 83·5% respectively. The positive predictive value was 94·3%. Our findings provide a non-invasive and simple tool to quickly categorize symptomatic patients as either COVID-19-probable or -improbable especially when RT-PCR and/or chest CT are not rapidly available.
Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Linfócitos/metabolismo , Programas de Rastreamento , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico por imagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Tomografia Computadorizada por Raios XAssuntos
DNA/genética , Doenças Hereditárias Autoinflamatórias/genética , Mutação , Enzimas Ativadoras de Ubiquitina/genética , Idoso , Análise Mutacional de DNA , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Masculino , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.
Assuntos
Síndromes Mielodisplásicas , Estruturas R-Loop , Humanos , Fator de Processamento U2AF/genética , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de RNA/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Mutação , Fatores de Transcrição/genética , Fosfoproteínas/genéticaRESUMO
Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.
Assuntos
Inflamassomos , Monócitos , Síndromes Mielodisplásicas , Dermatopatias Genéticas , Adulto , Humanos , Inflamassomos/genética , Estudos Prospectivos , Células Mieloides , MutaçãoRESUMO
BACKGROUND: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement. RESEARCH QUESTION: What are the pleuropulmonary manifestations in VEXAS syndrome? STUDY DESIGN AND METHODS: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others. RESULTS: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort. INTERPRETATION: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis.
Assuntos
Fibrose Pulmonar , Vacúolos , Masculino , Humanos , Idoso , Feminino , Prednisona , Pulmão/diagnóstico por imagem , Pulmão/patologia , Fibrose Pulmonar/patologia , Síndrome , MutaçãoRESUMO
Fever, inflammation and vacuoles in hematopoietic cells represent the main features associated with VEXAS syndrome, a new prototype of autoinflammatory disorders genetically characterized by somatic mutation of the UBA1 gene which encodes the enzyme1-activating enzyme (E1) required for ubiquitin signaling. Described very recently, patients with VEXAS syndrome present a systemic autoinflammatory syndrome associated with hematological impairments, especially cytopenias whose pathophysiology is mainly non-elucidated. Initially diagnosed in elderly male patients, VEXAS syndrome was frequently associated with a diagnosis of myelodysplastic syndromes (MDS) leading the medical community to first consider VEXAS syndrome as a new subtype of MDS. However, since the first description of VEXAS patients in 2021, it appears from the multitude of case reports that MDS associated with VEXAS are different from the classically described MDS.
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INTRODUCTION: The additional sex combs like 1 (ASXL1) gene is frequently mutated in a number of haematological neoplasms. The c.1934dupG, known to be the most common alteration in ASXL1, is associated with poor clinical outcome. A systematic determination of ASXL1 mutational status in myeloid malignancies is therefore necessary for prognostic stratification. METHODS: Because direct sequencing is not sensitive and next-generation sequencing (NGS) is time-consuming, expensive and sometimes does not allow the detection of the c.1934dupG, we have developed a fragment analysis assay, complementary to NGS, that allows the detection of c.1934dupG mutation in addition to other nearby insertions/deletions of ASXL1 located close to it. We called this assay the "PCR-Fluo-ASXL1-FA." RESULTS: First, we evaluated the efficiency of our approach compared to NGS and Sanger. We showed that "PCR-Fluo-ASXL1-FA" could detect all insertional mutations of ASXL1 located on its area, with a high sensitivity (1.5%). Then, we have illustrated the interest of this technique by three concrete cases. DISCUSSION: In summary, we have established a fragment analysis approach, which can detect most ASXL1 mutations, in particular the c.1934dupG, in a sensitive, fast and inexpensive manner. We therefore recommend the synchronous use of this method with NGS, to ensure complete detection of all clinically relevant ASXL1 mutations in patients suffering with myeloid neoplasms.