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Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of thrombotic and hemorrhagic events, that represent the leading causes of mortality and morbidity. Currently, while thrombotic risk is assessed through the IPSET-t and r-IPSET scores, there is no specific prognostic tool used to predict hemorrhagic risk in ET. The aim of the study was to define incidence and risk factors connected to hemorrhagic events by retrospectively analyzing 308 ET patients diagnosed between 1996 and 2022 at the Division of Hematology of Udine and treated according to the current international guidelines. According to molecular status, 193 patients (62.7%) were JAK2 mutated, 66 (21.4%) had a CALR mutation, 14 (4.5%) had a MPL mutation, 21 patients (6.8%) were "triple negative," and 14 patients (4.5%) were not evaluable. According to IPSET-t score, 49.7% patients were at high, 24.3% at intermediate, and 26.0% at low-risk, respectively. Twelve (3.9%) patients experienced bleeding at ET diagnosis, while 24 (7.8%) had at least one hemorrhagic event during follow-up at a median time of 103 months (range: 1-309). Forty hemorrhagic events were totally recorded and defined as minor in 22 cases, moderate in 11 cases, and severe in 7 cases. Cumulative incidence (CI) of hemorrhage at 10 and 20 years was 6.0% and 12.0%, respectively. A statistically significant correlation between hemorrhagic risk and IPSET-t score emerged: 10 years hemorrhage CI was 3.2% for low-risk, 2.9% for intermediate-risk, and 9.8% for high-risk patients, respectively (p=0.002). We found no correlation between hemorrhagic risk and gender or mutational status. Results of our study highlight the validity of IPSET-t score in predicting individual hemorrhagic risk among ET patients, suggesting a possible role of IPSET-t scoring system as a global evaluator for vascular events in ET patients.
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Trombocitemia Essencial , Trombose , Humanos , Trombocitemia Essencial/complicações , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Estudos Retrospectivos , Trombose/epidemiologia , Fatores de Risco , Prognóstico , Hemorragia/etiologia , Hemorragia/complicações , Mutação , Janus Quinase 2/genética , Calreticulina/genéticaRESUMO
Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.
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BACKGROUND: Pulmonary embolism (PE) without overt deep vein thrombosis (DVT) was common in hospitalized coronavirus-induced disease (COVID)-19 patients and represented a diagnostic, prognostic, and therapeutic challenge. The aim of this study was to analyze the prognostic role of PE on mortality and the preventive effect of heparin on PE and mortality in unvaccinated COVID-19 patients without overt DVT. METHODS: Data from 401 unvaccinated patients (age 68 ± 13 years, 33% females) consecutively admitted to the intensive care unit or the medical ward were included in a retrospective longitudinal study. PE was documented by computed tomography scan and DVT by compressive venous ultrasound. The effect of PE diagnosis and any heparin use on in-hospital death (primary outcome) was analyzed by a classical survival model. The preventive effect of heparin on either PE diagnosis or in-hospital death (secondary outcome) was analyzed by a multi-state model after having reclassified patients who started heparin after PE diagnosis as not treated. RESULTS: Median follow-up time was 8 days (range 1-40 days). PE cumulative incidence and in-hospital mortality were 27% and 20%, respectively. PE was predicted by increased D-dimer levels and COVID-19 severity. Independent predictors of in-hospital death were age (hazards ratio (HR) 1.05, 95% confidence interval (CI) 1.03-1.08, p < 0.001), body mass index (HR 0.93, 95% CI 0.89-0.98, p = 0.004), COVID-19 severity (severe versus mild/moderate HR 3.67, 95% CI 1.30-10.4, p = 0.014, critical versus mild/moderate HR 12.1, 95% CI 4.57-32.2, p < 0.001), active neoplasia (HR 2.58, 95% CI 1.48-4.50, p < 0.001), chronic obstructive pulmonary disease (HR 2.47; 95% CI 1.15-5.27, p = 0.020), respiratory rate (HR 1.06, 95% CI 1.02-1.11, p = 0.008), heart rate (HR 1.03, 95% CI 1.01-1.04, p < 0.001), and any heparin treatment (HR 0.35, 95% CI 0.18-0.67, p = 0.001). In the multi-state model, preventive heparin at prophylactic or intermediate/therapeutic dose, compared with no treatment, reduced PE risk and in-hospital death, but it did not influence mortality of patients with a PE diagnosis. CONCLUSIONS: PE was common during the first waves pandemic in unvaccinated patients, but it was not a negative prognostic factor for in-hospital death. Heparin treatment at any dose prevented mortality independently of PE diagnosis, D-dimer levels, and disease severity.
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BACKGROUND: Polymicrobial bloodstream infections (pBSI) occurring in hematological patients are still poorly understood, and specific information are very limited. OBJECTIVES AND METHODS: In this epidemiologic survey, we describe clinical characteristics and outcome of 125 consecutive pBSI occurred in oncohematological patients. Polymicrobial bloodstream infections (pBSI) were defined with the isolation of 2 or more bacteria from blood culture specimens obtained within 72 h. RESULTS: Over an 11-year period, we documented 500 bacterial bloodstream infections (BSI) in 4542 hospital admissions and 25% (125) of these were pBSI. Most common underlying hematological disease was acute myeloid leukemia and 89% of patients had severe neutropenia. Fifty pBSI (40%) occurred in patients undergoing a stem cell transplantation (SCT), mostly within 30 days from transplant (42/50-84%). Principal bacterial association was Gram-positive plus Gram-negative (57%). Resolution rate of pBSI was 82%, without differences between SCT and non-SCT cases. pBSI-related mortality was 15% (6% in SCT cases). Septic shock occurred in 16% of cases and septic shock-related mortality was 65% (75% in SCT cases and 63% in non-SCT cases; p = 0.6). Multidrug-resistant (MDR) bacteria were involved in 22% of pBSI and the MDR-pBSI-related mortality was significantly higher in SCT patients (p = 0.007). CONCLUSIONS: This observational study highlights that pBSI is not a rare bloodstream infectious complication in oncohematological patients. pBSI-related mortality is lower than 20%, but, if septic shock occurs, mortality reaches 65%. MDR bacteria were involved in 22% of cases and pBSI-MDR-related mortality was significantly higher in SCT patients.
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Bacteriemia , Infecções Bacterianas , Sepse , Bacteriemia/epidemiologia , Bactérias , Farmacorresistência Bacteriana Múltipla , Humanos , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVES: To assess the role that real-time therapeutic drug monitoring (TDM)-guided optimization of continuous-infusion (CI) meropenem may have in maximizing empirical treatment and in preventing breakthrough infection and/or colonization with carbapenem-resistant Enterobacteriaceae (CRE) among oncohaematological patients with febrile neutropenia (FN). METHODS: A monocentric, interventional, prospective study was conducted. The pharmacodynamic (PD) target was a steady-state meropenem concentration-to-MIC ratio (Css/MIC) of 4-8. The primary endpoint was 14 day all-cause mortality. The secondary endpoint was the prevalence of CRE colonization in rectal swabs of patients rehospitalized within 3 months. RESULTS: Among the 75 patients enrolled, most (56%) had AML, almost half (37/75, 49.3%) underwent HSCT and one-third (32%) received meropenem as monotherapy. Meropenem dosages were adjusted in 30.1% of TDM reassessments. Gram-negative infections were microbiologically documented in 20.0% of patients. All of the 12 patients having infections caused by in vitro meropenem-susceptible pathogens attained the desired PD target and were cured. Three patients had infections caused by in vitro meropenem-resistant pathogens. Two of these achieved a Css/MIC target of 1 and were cured; the other one achieved a suboptimal PD target (0.59) and died. The 14 day all-cause mortality (10.7%) was significantly associated, at multivariate regression, with HSCT (OR 0.086, 95% CI 0.008-0.936, P = 0.044) and with augmented renal clearance (OR 10.846, 95% CI 1.534-76.672, P = 0.017). None of the patients who had hospital readmissions in the 3 month follow-up (63/75) had CRE colonization in rectal swabs. CONCLUSIONS: Real-time TDM-guided CI meropenem may be a useful approach for attaining adequate exposure and preventing CRE emergence in FN oncohaematological patients.
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Monitoramento de Medicamentos , Neutropenia Febril , Antibacterianos , Neutropenia Febril/tratamento farmacológico , Humanos , Infusões Intravenosas , Meropeném , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Tienamicinas , Resultado do TratamentoRESUMO
BACKGROUND: Acute myeloid leukaemia (AML) patients are at high risk of invasive aspergillosis (IA) after first induction chemotherapy (CHT). Although IA risk factors have been identified, few data are available on impact of IA, occurring during induction phase, on overall AML outcome. PATIENTS AND RESULTS: The end point of this multicentre, case-control, study was to evaluate whether IA, occurring after first induction CHT, can affect treatment schedule and patient's outcome. We identified 40 AML patients (cases) who developed IA during first induction phase, 31 probable (77.5%) and 9 proven (22.5%). These cases were matched with a control group (80 AML) without IA, balanced according to age, type of CHT, AML characteristics and cytogenetic-molecular risk factors. The overall response rate to induction CHT was the same in the 2 groups. In the 40 cases with IA, the overall response rate to antifungal treatment was favourable (80%) but it was significantly affected by the achievement of leukaemia complete remission (CR) with induction CHT. In fact, in cases with AML responsive to induction CHT, responses of IA to antifungal therapy were 96% compared to 21% in cases of AML not responsive to induction treatment (P < .0001). The adherence to the schedule and full doses of CHT were reported in 35% of cases (14/40) and in 76% of controls (61/80) (P = .0001; OR 6.7; 95% CI 2.7-16.6). After first induction CHT, a significant higher number of cases (15/40; 37.5%) compared to controls (9/80; 11%) could not receive additional cycles of CHT (P = .0011, OR 4.8; 95% CI 1.9-12.3). The IA-related mortality was 22.5%. The median OS of cases was significantly worse than OS of controls with a difference of 12.3 months (12.1 vs 24.4 months, P = .04). However, the occurrence of IA during first induction phase did not have a significant impact on the OS of cases who achieved a CR of AML with induction CHT which are able to proceed, despite the IA, with their therapeutic program, achieving the same OS as the control group with AML in CR (P = ns). CONCLUSIONS: These data show that IA during first induction CHT can delay the subsequent therapeutic program and has a significant impact on OS, specifically in AML patients who did not achieved a CR of AML with the first course of CHT.
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Infecções Fúngicas Invasivas , Leucemia Mieloide Aguda/complicações , Idoso , Antifúngicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aspergilose/tratamento farmacológico , Aspergilose/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Quimioterapia de Indução , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/etiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mortalidade , Indução de Remissão , Resultado do TratamentoRESUMO
Objectives: To assess the population pharmacokinetics (popPK) of daptomycin at the conventional dose of 6 mg/kg/day in a cohort of oncohaematological patients. Methods: Patients underwent serial blood sampling on day 3 of therapy (before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9 and 12 h after dosing) to assess the pharmacokinetic profile of daptomycin. PopPK and Monte Carlo simulation were performed to define the probability of target attainment (PTA) with 6, 8, 10 and 12 mg/kg/day of the pharmacokinetic/pharmacodynamic target of AUC 24 /MIC >1081. Results: Thirty patients were recruited. A two-compartment open model with first-order intravenous input and first-order elimination was developed. Estimated creatinine clearance (CL CR ), serum albumin concentration (Alb) and presence of AML were covariates included in the final model. Monte Carlo simulation showed that the conventional 6 mg/kg/day dose resulted in optimal PTAs (≥80%) in the presence of pathogens with an MIC up to 0.5 mg/L only in patients with CL CR 50-100 mL/min/1.73 m 2 , Alb 26-45 g/L and a haematological diagnosis other than AML. Conversely, higher dosages, up to 12 mg/kg/day, were needed to achieve this goal in the presence of pathogens with an MIC of 0.25-0.5 mg/L in all of the other tested scenarios. In patients with CL CR 101-150 mL/min/1.73 m 2 and Alb 15-25 g/L, suboptimal PTAs (<60%) were predicted even with 12 mg/kg/day dosing . Conclusions: Our study provides a strong rationale for considering daptomycin dosages of ≥â¯8 mg/kg/day in several clinical scenarios for oncohaematological patients. In some of these scenarios therapeutic drug monitoring could be a useful adjunct for optimized care.
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Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Daptomicina/administração & dosagem , Daptomicina/farmacocinética , Neoplasias Hematológicas/complicações , Adulto , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Plasma/química , Estudos ProspectivosAssuntos
Anfotericina B/administração & dosagem , Infecções Fúngicas do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Voriconazol/administração & dosagem , Adolescente , Adulto , Aloenxertos , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Infecções Fúngicas do Sistema Nervoso Central/etiologia , Infecções Fúngicas do Sistema Nervoso Central/mortalidade , Criança , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy ("3+7" daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m2 for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m2 for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2-11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9-19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2-11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9-19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged >68 years (HR = 0.34, 95% CI: 0.13-0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15-0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged >68 years.
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Bloodstream infections (BSI) caused by Gram-negative bacteria (GNB) in patients with hematological malignancies (HM) have been associated with high mortality rates, particularly with infections caused by antibiotic-resistant strains. A multicenter cohort study including all consecutive episodes of GNB BSI in HM patients was conducted to update the epidemiology and antibiotic resistance patterns (compared to our previous survey conducted between 2009 and 2012) and investigate risk factors for GNB BSI due to multidrug-resistant (MDR) isolates. A total of 834 GNB were recovered in 811 BSI episodes from January 2016 to December 2018. Compared to the previous survey, there was a significant reduction in use of fluoroquinolone prophylaxis and a significant recovery in susceptibility rates to ciprofloxacin among Pseudomonas aeruginosa, Escherichia coli and Enterobacter cloacae isolates. In addition, there was a shift to a significantly increased susceptibility of P. aeruginosa isolates to ceftazidime, meropenem, and gentamicin. A total of 256/834 (30.7%) isolates were MDR. In multivariable analysis, MDR bacteria culture-positive surveillance rectal swabs, previous therapy with aminoglycosides and carbapenems, fluoroquinolone prophylaxis, and time at risk were independently associated with MDR GNB BSI. In conclusion, despite the persistence of a high prevalence of MDR GNB, there was a shift to a reduced use of fluoroquinolone prophylaxis and increased rates of susceptibility to fluoroquinolones in almost all isolates and to almost all antibiotics tested among P. aeruginosa isolates, compared to our previous survey. Fluoroquinolone prophylaxis and previous rectal colonization by MDR bacteria were independent risk factors for MDR GNB BSI in the present study.
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Infecções por Bactérias Gram-Negativas , Neoplasias Hematológicas , Sepse , Humanos , Estudos de Coortes , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Sepse/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Fatores de Risco , Neoplasias Hematológicas/complicações , ItáliaAssuntos
Biomarcadores Tumorais , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda , Mutação , Proteínas WT1 , Tirosina Quinase 3 Semelhante a fms , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Neoplasia Residual , Taxa de Sobrevida , Proteínas WT1/genética , Proteínas WT1/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.
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BACKGROUND: The hypomethylating agent Decitabine (DAC) is a valuable treatment option in acute myeloid leukemia (AML), particularly in elderly patients (pts) not suitable for intensive chemotherapy (CHT). However, limited data are available about efficacy and safety of DAC in clinical practice. PATIENTS AND METHODS: We retrospectively reviewed data of 104 AML pts treated with DAC in eight Italian Hematological Centers from 2015 to 2017. The objective of this study was to evaluate the efficacy and safety of DAC in older AML pts outside of clinical trial. Seventy-five (75%) pts received DAC as first line treatment (Cohort 1) and 29 pts as salvage therapy (Cohort 2). All pts received a DAC schedule of 20 mg/sqm IV for 5-days, every 28 days. The median age was 72.5 years (74 in cohort 1 and 66 in cohort 2) and 16% of pts had an ECOG performance status >2 at the start of DAC treatment (with non-significant difference in the two cohorts). The cumulative illness rating scale (CIRS) was > 6 in 27% of pts. Forty-five pts (43%) had secondary AML. Bone marrow blast count was > 30% in 64% of patients (67/104). In the relapsed cohort 17/29 (59%) patients were treated with DAC after conventional CHT, 5/29 (17%) after allo-SCT and 7/29 (24%) after azacitidine therapy. RESULTS: A total of 469 DAC cycles were given to the 104 pts with a median of 3 cycles (range 1-21) and 45/104 (43%) pts received > 4 cycles. The Overall Response Rate (ORR = Complete Remission-CR plus Partial Remission-PR) was 33%, significantly higher in Cohort 1 (42%) compared to Cohort 2 (14%) (p = 0.009). The median duration of response was 6 months (range 1-20). In Cohort 1 the best response (CR or PR) was obtained between 3th and 6th cycle. In multivariate Cox regression analysis, achievement of CR or PR (HR = 0.78; p = 0.0004), CIRS < 6 (HR = 0.9; p = 0.04) and complex karyotype (HR = 0.8; p = 0.03) were significant predictors of better overall survival (OS). Median OS from the start of DAC therapy was 11 months for the whole population with a significant OS advantage in Cohort 1 (median OS 12.7 mths vs 6.3 mths; p = 0.003); median OS was significantly longer in responders compared to non-responders (22.6 mths vs 5.7 mths; p < 0.0001). At the last follow-up, 56 patients (54%) are still alive and 48 (46%) are dead (71% due to disease progression). The most common toxicities were myelosuppression and documented infectious complications that occurred mainly during the first 4 cycles. CONCLUSION: These data confirm the efficacy (ORR 33%) and the acceptable safety profile of DAC in the real life management of AML in elderly pts unsuitable for intensive CHT, with a significant better performance in first line therapy (ORR 42%, median OS 12.7 mths). The efficacy of DAC, both in first line and as salvage therapy, may probably be improved with combined treatment strategies and/or with different DAC schedules that could increase its anti-leukemic effect.
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Antimetabólitos Antineoplásicos/uso terapêutico , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Feminino , Humanos , Itália , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Bloodstream infections (BSIs) remain life-threatening complications in the clinical course of patients with haematological malignancies (HM) and Escherichia coli represent one of the most frequent cause of such infections. In this study, we aimed to describe risk factors for resistance to third generation cephalosporins and prognostic factors, including the impact of third generation cephalosporins resistance, in patients with HM and BSIs caused by E. coli. Three hundred forty-two cases of E. coli BSIs were collected during the study period (from January 2016 to December 2017). The percentage of resistance to third generation cephalosporins was 25.7%. In multivariate analysis, the variables recent endoscopic procedures, culture-positive surveillance rectal swabs for multidrug-resistant bacteria, antibiotic prophylaxis with fluoroquinolones, and prolonged neutropenia were independently associated with bloodstream infections caused by a third generation cephalosporins resistant E. coli. The overall 30-day mortality rate was 7.1%. Cox regression revealed that significant predictors of mortality were acute hepatic failure, septic shock, male sex, refractory/relapsed HM, and third generation cephalosporins resistance by E. coli isolate. In conclusion, resistance to third generation cephalosporins adversely affected the outcomes of bloodstream infections caused by E. coli in our cohort of HM patients. We also found a significant correlation between prophylaxis with fluoroquinolones and resistance to third generation cephalosporins by E. coli isolates.
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Infecções por Escherichia coli/epidemiologia , Escherichia coli/patogenicidade , Neoplasias Hematológicas/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Antibioticoprofilaxia , Bacteriemia/microbiologia , Cefalosporinas/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/sangue , Feminino , Fluoroquinolonas/uso terapêutico , Neoplasias Hematológicas/complicações , Humanos , Controle de Infecções , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neutropenia/complicações , Estudos Prospectivos , Fatores de RiscoRESUMO
We analyzed the outcome of allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML) patients according to molecular Minimal Residual Disease (MRD) status prior to allo-SCT. MRD was assessed by the quantitative expression of the pan-leukemic marker Wilms' tumor (WT1) gene, according to the validated LeukemiaNet method. Between 2005 and 2016, 122 consecutive AML patients, WT1 positive at diagnosis, received allo-SCT in cytologic complete remission (cCR). The median age at SCT was 53 years (range 18-70). Quantitative analysis of WT1 gene expression (bone marrow samples) was available in all cases both at diagnosis (100% of samples overexpressed WT1 with a mean of 8607±8187 copies/104 Abelson) and immediately before allo-SCT. Eighty one cases (66%) were MRD-WT1 negative (WT1 <250 copies) and 41/122 (44%) cases were MRD-WT1 positive (WT1 >250 copies) prior to allo-SCT. We evaluated post-SCT overall survival (OS), disease free survival (DFS) and relapse rate (RR), according to MRD-WT1 status pre-SCT. Both post-allo-SCT OS and DFS were significantly improved in patients who were MRD-WT1 negative at the time of SCT compared with those who were MRD-WT1 positive, with a median OS and DFS not reached in the MRD-WT1 negative group and 9 and 8 months, respectively, in the WT1 positive group (OS log-rank p<0.0001; hazard ratio [HR] 3.9, 95% confidence interval [95% CI] 2.0-7.38; DFS log-rank p<0.0001; HR 3.73, 95% CI 2.0-6.72). The RR after SCT was 15% (12/81) in pre-SCT MRD-WT1 negative cases and 44% (18/41) in MRD-WT1 positive cases (p=0.00073). Univariate analysis showed that MRD-WT1 negativity pre-SCT and grade <2 acute GVHD were significant prognostic factors for improved OS and DFS. However multivariate analysis showed MRD-WT1 negativity pre-SCT was the only independent prognostic factor for improved OS and DFS. These data show that pre allo-SCT molecular MRD evaluation using WT1 expression is a powerful predictor of post allo-SCT outcomes in AML undergoing SCT in cCR. Patients with both cCR and MRD-WT1 negativity before SCT have a very good outcome with lower RR and improved OS. The pre allo-SCT MRD-WT1 stratification in AML is a valuable tool to identify patients at high risk of post-SCT relapse, and can influence conditioning regimen intensification and/or post-SCT preemptive strategies.
Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia Mieloide Aguda/patologia , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Transplante de Células-Tronco , Proteínas WT1/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/terapia , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Transplante Homólogo , Proteínas WT1/genética , Adulto JovemRESUMO
The FMS-like tyrosine kinase 3 (FLT3) mutation in acute myeloid leukemia (AML) is a negative prognostic factor and, in these cases, allogeneic stem cell transplantation (allo-SCT) can represent an important therapeutic option, especially if performed in complete remission (CR). However, it is increasingly clear that not all cytological CRs (cCRs) are the same and that minimal residual disease (MRD) before allo-SCT could have an impact on AML outcome. Unfortunately, FLT3, due its instability of expression, is still not considered a good molecular MRD marker. We analyzed the outcome of allo-SCT in a population of FLT3-positive AML patients according to molecular MRD at the pretransplantation workup, assessed by the quantitative expression evaluation of the panleukemic marker Wilms' tumor (WT1) gene. Sixty-two consecutive AML FLT3-positive patients received allo-SCT between 2005 and 2016 in our center. The median age at transplantation was 55 years. The quantitative analysis of the WT1 gene expression (bone marrow samples) was available in 54 out of 62 (87%) cases, both at diagnosis (100% overexpressing WT1 with a mean of 9747 ± 8064 copies) and before allo-SCT (33 WT1-negative and 21 WT1-positive cases at the pretransplantation workup). Of these cases, 33/54 (61%) were both in cCR and molecular remission (WT1-negative) at the time of transplantation, 13/54 (24%) were in cCR but not in molecular remission (WT1-positive), and 8/54 (15%) showed a cytological evidence of disease (relapsed or refractory). Both post-allo-SCT overall survival (OS) and disease-free survival (DFS) were significantly better in patients who were WT1-negative (WT1 <250 copies) at the time of transplantation compared with those who were WT1-positive (WT1 >250 copies), with a median OS and DFS not reached in the WT1-negative group and 10.2 and 5.5 months, respectively, in the WT1-positive group (OS log-rank p = 0.0005; hazard ratio [HR] = 3.7, 95% confidence interval [95% CI] = 1.5-9; DFS log-rank p = 0.0001; HR = 4.38, 95% CI = 1.9-10). Patients with cCR who were WT1-positive had the same negative outcome as those with a cytological evidence of disease. The relapse rate after allo-SCT was 9% (3/33) in pre-allo-SCT WT1-negative cases and 54% (7/13) in WT1-positive cases (p = 0.002). At multivariate analysis, WT1 negativity before allo-SCT and grade <2 acute graft versus host disease were the only independent prognostic factors for improved OS and DFS. These data show that pre-allo-SCT molecular MRD evaluation through WT1 expression is a powerful predictor of posttransplantation outcomes (OS, DFS, relapse rate). Patients with both cCR and a WT1-negative marker before allo-SCT have a very good outcome with very low relapse rate; conversely, patients with positive molecular MRD and refractory/relapsed patients have a negative outcome. The WT1 MRD stratification in FLT3-positive AML is a valuable tool with which to identify patients who are at high risk of relapse and that could be considered from post-allo-SCT prophylaxis with FLT3 inhibitors or other strategies (donor lymphocyte infusion, tapering of immunosuppression, azacitidine).