RESUMO
The present case reports a bacteremia due to Lachnoanaerobaculum umeaense (a Gram-positive, filamentous, rod-shaped, anaerobic, spore-forming bacillus present in the human oral microbiota) in a patient treated for acute myeloid leukemia. After failed identification by MALDI-TOF, identification was done by sequencing of 16s rRNA. The patient was successfully treated with Amoxicillin-clavulanic acid and ciprofloxacin for seven days. Comparison of V1-V3 regions of the bacterial 16S rRNA gene gene with published sequences failed to classify the strain as pathogenic or non-pathogenic based on this phylogenetic classification alone. Although Lachnoanaerobaculum gingivalis are known to be associated with bacteremia in patients with acute myeloid leukemia, this clinical case of infection by L. umeaense argues for further studies that will lead to more efficient classification of the infection by these microorganisms.
Assuntos
Antibacterianos , Bacteriemia , Leucemia Mieloide Aguda , RNA Ribossômico 16S , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/complicações , Bacteriemia/microbiologia , Bacteriemia/tratamento farmacológico , Bacteriemia/diagnóstico , RNA Ribossômico 16S/genética , Antibacterianos/uso terapêutico , Masculino , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/diagnóstico , Filogenia , Ciprofloxacina/uso terapêutico , Pessoa de Meia-Idade , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêuticoRESUMO
Very few data are available about hypomethylating agent (HMA) efficiency in core binding factor acute myeloid leukemias (CBF-AML). Our main objective was to evaluate the efficacy and safety of HMA in the specific subset of CBF-AML. Here, we report the results of a multicenter retrospective French study about efficacy of HMA monotherapy, used frontline or for R/R CBF-AML. Forty-nine patients were included, and received a median of 5 courses of azacitidine (n = 46) or decitabine (n = 3). ORR was 49% for the whole cohort with a median time to response of 112 days. After a median follow-up of 72.3 months, median OS for the total cohort was 10.6 months. In multivariate analysis, hematological relapse of CBF-AML at HMA initiation was significantly associated with a poorer OS (HR: 2.13; 95%CI: 1.04-4.36; p = 0.038). Responders had a significantly improved OS (1-year OS: 75%) compared to non-responders (1-year OS: 15.3%; p < 0.0001). Hematological improvement occurred for respectively 28%, 33% and 48% for patients who were red blood cell or platelet transfusion-dependent, or who experienced grade 3/4 neutropenia at HMA initiation. Adverse events were consistent with the known safety profile of HMA. Our study highlights that HMA is a well-tolerated therapeutic option with moderate clinical activity for R/R CBF-AML and for patients who cannot handle intensive chemotherapy.
Assuntos
Azacitidina , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Decitabina/uso terapêutico , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Ligação ao Core , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do TratamentoRESUMO
We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Adulto , Humanos , Estudos Retrospectivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Recidiva Local de Neoplasia/etiologia , Leucemia Mieloide Aguda/complicações , Transplante de Células-Tronco Hematopoéticas/métodos , Segunda Neoplasia Primária/etiologia , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/etiologia , Receptores de Complemento 3bRESUMO
Acute myeloid leukemia (AML) with BCR::ABL1 has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis chronic myeloid leukemia (BC-CML) without evidence of a chronic phase (CP), remains challenging. We aimed to better characterize this entity by integrating clonal architecture analysis, mutational landscape assessment, and gene expression profiling. We analyzed a large retrospective cohort study including CML and AML patients. Two AML patients harboring a BCR::ABL1 fusion were included in the study. We identified BCR::ABL1 fusion as a primary event in one patient and a secondary one in the other. AML-specific variants were identified in both. Real-time RT-PCR experiments demonstrated that CD25 mRNA is overexpressed in advanced-phase CML compared to AML. Unsupervised principal component analysis showed that AML harboring a BCR::ABL1 fusion was clustered within AML. An AML vs. myeloid BC-CML differential expression signature was highlighted, and while ID4 (inhibitor of DNA binding 4) mRNA appears undetectable in most myeloid BC-CML samples, low levels are detected in AML samples. Therefore, CD25 and ID4 mRNA expression might differentiate AML with BCR::ABL1 from BC-CML and assign it to the AML group. A method for identifying this new WHO entity is then proposed. Finally, the hypothesis of AML with BCR::ABL1 arising from driver mutations on a BCR::ABL1 background behaving as a clonal hematopoiesis mutation is discussed. Validation of our data in larger cohorts and basic research are needed to better understand the molecular and cellular aspects of AML with a BCR::ABL1 entity.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Humanos , Crise Blástica/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , RNA MensageiroRESUMO
KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols, and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of comutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in 3 consecutive trials from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%; P = .001) and OS (28.1% vs 60.7%; P = .006) rates. Next, we analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements and KMT2A genomic fusion as markers. In approximately one-third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. In contrast, KMT2A-based MRD was highly reliable and strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR, 7.1%; OS, 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adulto , Neoplasia Residual/genética , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva , Imunoglobulinas , Medição de RiscoRESUMO
Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto Jovem , Humanos , Estudos Prospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Ciclofosfamida , Sistema Nervoso Central , Resultado do TratamentoRESUMO
We investigated single nucleotide polymorphisms (SNPs) possibly involved in immune reconstitution inflammatory syndrome of chronic disseminated candidiasis (IRIS-CDC) through a candidate gene approach and a prospective matched-control study. We found that an SNP located in interleukin-1B at rs1143627 was significantly associated with the risk of developing IRIS-CDC.
RESUMO
INTRODUCTION: Positive urine sample is a frequent finding in post-chemotherapy febrile neutropenia (FN) and can lead to prolonged antibiotic therapy. The aim of this study was to assess the outcome of bacteriuria episodes in FN patients receiving targeted antibiotic therapy. MATERIALS AND METHODS: A multi-centric retrospective study was conducted over a four-year period (2014-2019) on systematic urinalysis. All consecutive first bacteriuria episodes (≤ 2 bacteria with at least ≥ 103 CFU/mL) during FN in hospitalized adult patients for hematological malignancies were included. Relapse and recurrence were defined by fever or urinary tract symptoms (UTS) with the same bacterial subspecies in urine occurring ≤ 7 days and ≤ 30 days, respectively, after antibiotic discontinuation. Mortality rate was determined at 30 days. Targeted antibiotic therapy ≤ 10 days for women and ≤ 14 for men was considered as short course. RESULTS: Among 97 patients, 105 bacteriuria episodes on systematic urinalysis were analyzed; 67.6% occurred in women, 41.9% in AML patients, 17.1% were bacteremic, 14.2% presented with UTS, and 61.9% were treated with short-course antibiotic treatment. One death was reported. In men, no relapse/recurrence was noted, even in the short-course antibiotic group. In women, 2.8% of episodes treated with short-course antibiotic led to relapse or recurrence. CONCLUSIONS: Relapse, recurrence, and mortality were uncommon events in FN patients experiencing bacteriuria episode, whatever the antibiotic duration. To distinguish asymptomatic bacteriuria from infection remained challenging in women. In men, systematic urinalysis at onset of FN could be useful.
Assuntos
Bacteriúria , Neutropenia Febril , Hematologia , Infecções Urinárias , Adulto , Masculino , Humanos , Feminino , Bacteriúria/tratamento farmacológico , Bacteriúria/etiologia , Bacteriúria/diagnóstico , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Antibacterianos/uso terapêutico , Febre/tratamento farmacológico , Febre/etiologia , Neutropenia Febril/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/etiologiaRESUMO
The treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch, and cell death. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (p < 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients.ClinicalTrials.gov identifier: NCT01999413.
Assuntos
Citarabina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico , Emulsões/uso terapêutico , Estudos de Viabilidade , Óleos de Peixe/uso terapêutico , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/genética , Fator 2 Relacionado a NF-E2/genéticaRESUMO
Although Francisella tularensis is a well-known, highly virulent bacterium that causes tularemia in humans, other Francisella species have been associated with sporadic human infections. We describe a human cutaneous infection with bacteremia caused by F. salimarina, a Francisella species recently identified from seawater and fishes, in an immunocompromised patient in France.
Assuntos
Bacteriemia , Francisella tularensis , Tularemia , Bacteriemia/diagnóstico , França , Humanos , Hospedeiro Imunocomprometido , Tularemia/diagnóstico , Tularemia/tratamento farmacológico , Tularemia/microbiologiaRESUMO
OBJECTIVES: There is no specific recommendation about antimicrobial treatment length for documented infections in chemotherapy induced febrile neutropenia (FN). Practices have changed along time in our center regarding length of antibiotic treatment. The aim of this study was to compare long versus short antibiotic course for bloodstream infection (BSI) treatment in acute myeloid leukemia (AML) patients during FN. METHODS: This monocentric retrospective comparative study included all consecutive BSI episodes among AML patients with FN for 3 years (2017-2019). Episodes were classified regarding the length of antibiotic treatment, considered as short course if the treatment lasted ≤ 7 days, except for nonfermenting bacteria and Staphylococcus aureus or lugdunensis for which the threshold was ≤ 10 days and ≤ 14 days, respectively. The primary outcome was the number of BSI relapses in both groups within 30 days of antibiotic discontinuation. RESULTS: Among 71 AML patients, 104 BSI episodes were included; 48 (46%) received short course treatment. Only 8 (7.6%) BSI episodes relapsed within 30 days of antibiotic discontinuation, 5 having received short course treatment. No association was found between risk of relapse and short course of antibiotic treatment (p = 0.37). The only risk factor significantly associated with BSI relapse was neutropenia duration (p = 0.005). CONCLUSION: Antibiotic short course seemed as effective as prolonged treatment for BSI in AML patients during FN, with very few relapses at day 30. These encouraging findings should be confirmed through prospective studies.
Assuntos
Bacteriemia , Neutropenia Febril , Leucemia Mieloide Aguda , Sepse , Antibacterianos/efeitos adversos , Bacteriemia/tratamento farmacológico , Neutropenia Febril/complicações , Neutropenia Febril/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Sepse/tratamento farmacológicoRESUMO
In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m2 of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.
Assuntos
Gemtuzumab/farmacologia , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Análise por Conglomerados , Análise Citogenética , Citogenética , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Indução de Remissão , Risco , Adulto JovemRESUMO
We retrospectively examined the results of a new chemo-free approach combining blinatumomab with ponatinib (blina/pona) in 26 relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients. All but one achieved complete morphologic remission, and 23 achieved a complete molecular response. With a median follow-up of 34.4 months, the median overall (OS) and event-free (EFS) survivals were 20 and 15.3 months, respectively. After blina/pona, 8 patients underwent an allotransplant (allo), while among the 18 non-transplanted cases, 15 received ponatinib in maintenance. Fifteen relapse/progressions occurred with a significant difference between allo and non allo cases (12.5% vs 82.3%, p = 0.003). However, OS and EFS were similar between both groups. Finally, blina/pona was well tolerated with eight reversible neurologic events and three cytokine release syndromes. Prospective studies are needed to properly assess the safety, tolerability and efficacy of the combination therapy.
Assuntos
Anticorpos Biespecíficos , Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Imidazóis , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Prospectivos , Piridazinas , Estudos RetrospectivosRESUMO
Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Trombocitemia Essencial , Genômica , Humanos , Mutação , Policitemia Vera/genética , Trombocitemia Essencial/genéticaRESUMO
The OPAL study is a French multicenter observational retrospective analysis of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia treated in a real-life setting by ponatinib. Twenty-nine patients were included since 2012. Median age was 55 years. The initial dose of ponatinib, combined to chemotherapy in half of the patients, was 45 mg/day in most instances. The remission rate was 90% and seven patients received allogeneic stem cell transplantation. Median disease-free and overall survival were only 3.5 and 9.9 months respectively. The outcome of patients with BCR-ABL mutation was similar to that of unmutated patients. With a median duration of exposure to ponatinib of 4 months, only 3 cardio-vascular events were recorded despite a high incidence of risk factors, and overall safety was acceptable. These results underline the place of ponatinib to induce early response in advanced disease and the need of new combinations to improve long-term outcome.
Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Imidazóis , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas , Estudos RetrospectivosAssuntos
Leucemia Mieloide Aguda , Proteínas de Ligação a DNA , Dioxigenases , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares , Nucleofosmina , Proteínas Proto-OncogênicasRESUMO
BACKGROUND: Chronic disseminated candidiasis (CDC) is a rare disease that mostly occurs after chemotherapy-induced prolonged neutropenia in patients with hematological malignancies. It is believed to ensue from Candida colonization, breach of the intestinal epithelial barrier, and venous translocation to organs. Fungal blood or liver biopsy cultures are generally negative, suggesting the absence of an ongoing invasive fungal disease. METHODS: To unravel the contribution of the immune system to CDC pathogenesis, we undertook a prospective multicentric exploratory study in 44 CDC patients at diagnosis and 44 matched controls. RESULTS: Analysis of Candida-specific T-cell responses using enzyme-linked immunospot assays revealed higher numbers of interferon (IFN)γ-producing T cells reactive to mp65 or candidin in 27 CDC cases compared with 33 controls. Increased plasma levels of soluble CD25, interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, and IL-10 and lower levels of IL-2 were observed in CDC patients versus controls. Neutrophilia and higher levels of CD4 and CD8 T-cell activation were found in CDC patients as well as increased proportions of CXCR3-expressing TCRγδâ+Vδ2+ cells. CONCLUSIONS: The expansion of Candida-specific IFNγ-producing T cells together with features of T-cell activation and systemic inflammation identified here support the view that CDC belongs to the broad spectrum of fungal-associated immune reconstitution inflammatory syndromes.
Assuntos
Candidíase Invasiva/etiologia , Candidíase Invasiva/imunologia , Neoplasias Hematológicas/complicações , Células Th1/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Síndrome Inflamatória da Reconstituição Imune/imunologia , Interferon gama/biossíntese , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/imunologia , Estudos ProspectivosRESUMO
A large variety of molecular rearrangements of the NUP98 gene have been described in the past decades (n = 72), involving fusion partners coding for different transcription factors, chromatin modifying enzymes, as well as various cytosolic proteins. Here, we report the case of an AML-M2 patient with a variant NUP98-LEDGF/PSIP1 gene fusion (N9-L10). In this patient, three different NUP98-LEDGF fusion mRNAs were characterized due to alternative splicing in LEDGF exon 11. Targeted high-throughput sequencing revealed the presence of IDH1, SRSF2, and WT1 additional pathogenic mutations. To improve the therapeutic monitoring, quantification of NUP98-LEDGF mRNA by real-time PCR was developed. Because of poor response to conventional chemotherapy, allogeneic stem cell transplantation was performed, followed by 20 cycles of azacitidine-based preemptive treatment of relapse. More than 31 months after diagnosis, corresponding to 25 months post SCT and 4 months after the last cycle of azacytidine, the patient is in complete molecular remission (undetectable NUP98-LEDGF mRNA transcripts). This study highlights the considerable variability in breakpoint location within both NUP98 and LEDGF, associated with alternative splicing affecting LEDGF. It also emphasizes the need to fully characterize the breakpoints within the two genes and the identification of all fusion mRNAs, particularly for the development of a molecular monitoring assay. All these data seem critical for the optimal management of NUP98-LEDGF + hematological malignancies commonly associated with a poor prognosis.