RESUMO
Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.
Assuntos
Aspirina , Esquema de Medicação , Hemorragia , Inibidores da Agregação Plaquetária , Trombocitemia Essencial , Humanos , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia/induzido quimicamente , Tromboxano B2/sangue , Ativação Plaquetária/efeitos dos fármacos , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.
Assuntos
Sobrecarga de Ferro , Mielofibrose Primária , Benzoatos/efeitos adversos , Deferasirox/uso terapêutico , Humanos , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/etiologia , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Pirazóis , Pirimidinas , Estudos RetrospectivosAssuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Crizotinibe/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Anaplásico de Células Grandes , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de SobrevidaRESUMO
INTRODUCTION: The Coronavirus disease 2019 (COVID-19) pandemic and the resulting social distancing, determined a reduction in access to care and limitations of individual freedom, with a consequent strong impact on quality of life (QoL), anxiety levels and medical management of onco-hematological people. In particular, in the case of patients with chronic myeloproliferative neoplasm (MPN), concern about SARS-CoV-2 infection added to the burden of symptoms (BS) which already weights on the QoL of these patients. We designed a cross-sectional survey in order to investigate the impact of the COVID-19 pandemic on status of anxiety, BS and QoL in MPN patients. METHODS: We analyzed the anxiety levels using the Zung Self-Rating Anxiety Scale (SAS); BS modifications were studied using the 18 items of the Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF]. RESULTS: 132 people answered to the survey: 27 (20.4%) patients achieved a moderate to marked anxiety index value: this group described a greater worsening of symptoms than the rest of the cohort (p <0.0001). Women showed a higher level of anxiety than men (p = 0.01). A trend for lower level of anxiety was reported by patients who performed habitual physical activity (p = 0.06). A total of 98 (74.2%) patients described worsening of their symptoms during the quarantine period; 94 (71.2%) patients had postponed appointments or visits: they showed a significant worsening of their BS (p =0.01). CONCLUSION: This study first showed that the COVID-19 quarantine had a significant negative impact on the level of anxiety and BS in MPN patients. We identified female gender, absence of physical activity, the need for frequent visit to the hospital and the absence of a direct access to healthcare staff as the main factors associated to a higher anxiety index and worst BS.
RESUMO
Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.
Assuntos
Etanolaminas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Linhagem Celular , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Quebras de DNA/efeitos dos fármacos , Complexo II de Transporte de Elétrons/efeitos dos fármacos , Complexo II de Transporte de Elétrons/metabolismo , Etanolaminas/metabolismo , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Mitocôndrias/genética , Mitocôndrias/patologia , Mutação , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido Succínico/metabolismo , Tigeciclina/farmacologiaRESUMO
We analyzed appearance of non transferrin bound iron (NTBI) in 30 transplant eligible patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) during conventional chemotherapy treatment program and evaluated possible relationship with transfusional body iron intake, iron parameters and clinical complications. For each course, serum samples for NTBI detection were taken prior to chemotherapy, during treatment and during subsequent bone marrow myelosuppression: NTBI was assessed by HPLC. Appearance of NTBI was observed from the start of induction treatment and was still detectable during bone marrow myelosuppression; the recovery of the bone marrow function coincided with the disappearance of NTBI. This kinetic was observed in all subsequent high doses chemotherapy courses, independently from confounding variables such as transfusional iron intake and transferrin saturation. NTBI seems to be a consequence of chemotherapy induced lysis of bone marrow cells and, partly, of hepatocytes after cytotoxic injury. The subsequent persistence of NTBI throughout bone marrow myelosuppression is related to the transient suspension of erythropoietic activity. Moreover, NTBI levels >2µM at the beginning of iatrogenic myelosuppression were associated with higher risk of sepsis caused by Gram negative Bacilli (RR 2.571), also compared with other infectious complications (RR 1.954).