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1.
Isr Med Assoc J ; 9(22): 491-497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954695

RESUMO

BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
2.
Isr Med Assoc J ; 9(22): 498-502, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954696

RESUMO

BACKGROUND: Progress in the treatment of breast cancer has led to substantial improvement in survival, but at the cost of increased side effects, with cardiotoxicity being the most significant one. The commonly used definition is cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction reduction of > 10%, to a value below 53%. Recent studies have implied that the incidence of CTRCD among patients with breast cancer is decreasing due to lower doses of anthracyclines and low association to trastuzumab and pertuzumab treatment. OBJECTIVES: To evaluate the prevalence of CTRCD among patients with active breast cancer and to identify significant associates for its development. METHODS: Data were collected as part of the Israel Cardio-Oncology Registry, which enrolls all patients who are evaluated at the cardio-oncology clinic at our institution. Patients were divided to two groups: CTRCD and no-CTRCD. RESULTS: Among 103 consecutive patients, five (5%) developed CTRCD. There were no significant differences in the baseline cardiac risk factors between the groups. Significant correlations of CTRCD included treatment with trastuzumab (P = 0.001) or pertuzumab (P < 0.001), lower baseline global longitudinal strain (GLS) (P = 0.016), increased left ventricular end systolic diameter (P < 0.001), and lower e' septal (P < 0.001). CONCLUSIONS: CTRCD is an important concern among patients with active breast cancer, regardless of baseline risk factors, and is associated with trastuzumab and pertuzumab treatment. Early GLS evaluation may contribute to risk stratification and allow deployment of cardioprotective treatment.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/epidemiologia , Disfunção Ventricular Esquerda/epidemiologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Cardiotoxicidade/etiologia , Feminino , Humanos , Israel , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente
3.
Int J Rheum Dis ; 23(8): 1030-1039, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32881350

RESUMO

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Idoso , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Vitória
4.
Trials ; 21(1): 758, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883328

RESUMO

OBJECTIVES: Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. TRIAL DESIGN: This trial is a phase 2, open label, two-stage, multicentre, randomised trial. PARTICIPANTS: Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 µgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. INTERVENTION AND COMPARATOR: Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose - 4mg/kg, infused over 60 minutes). MAIN OUTCOMES: The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. RANDOMISATION: Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. BLINDING: This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. NUMBERS TO BE RANDOMISED: In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. TRIAL STATUS: The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. TRIAL REGISTRATION: COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. FULL PROTOCOL: The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Progressão da Doença , Interações entre Hospedeiro e Microrganismos , Humanos , Intubação Intratraqueal , Irlanda , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
5.
Lancet Oncol ; 21(9): 1188-1200, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888452

RESUMO

BACKGROUND: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. METHODS: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. FINDINGS: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). INTERPRETATION: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche and AbbVie.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversos , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sulfonamidas/efeitos adversos , Resultado do Tratamento
6.
Trials ; 21(1): 772, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907638

RESUMO

OBJECTIVES: The main aim of the study is to evaluate the efficacy of a single dose of sarilumab, in subcutaneous administration, in hospitalised patients with moderate to early severe COVID-19 infection compared to the current standard of care, to prevent progression to systemic hyperinflammatory status. Our hypothesis is that use of subcutaneous sarilumab in early stages (window of opportunity) of COVID-19 moderate-severe pneumonia can prevent higher oxygenation requirements through non-invasive and invasive mechanical ventilation and decrease in-hospital stays, as well as death rate. The secondary objectives of the study are to evaluate the safety of sarilumab through hospitalisation and up to day 14 after discharge, compared to the control arm as assessed by incidence of serious and non serious adverse events (SAEs). In addition, as an exploratory objective, to compare the baseline clinical and biological parameters, including serum IL-6 levels, of the intervention population against controls of the same pandemic outbreak (using a propensity score) to search for markers that identify the best candidates for the treatment with subcutaneous IL-6R inhibitors and to attempt an approximation in the temporal frame of the "window of opportunity" TRIAL DESIGN: SARCOVID is an investigator-initiated single center randomised proof of concept study. PARTICIPANTS: Patients treated at the Hospital Universitario La Princesa, Madrid, Spain requiring hospitalisation will be consecutively recruited, meeting all inclusion criteria and none of the exclusion criteria Inclusion criteria a. Age >18, <80 years old b. COVID-19 infection documented by a positive RT-PCR test or, in absence of a RT-PCR positive test, case definition of COVID 19 infection/pneumonia as per local protocol and the presence of a positive serologic test (IgM/IgA by ELISA) c. Documented interstitial pneumonia requiring admission and at least two of the following parameters: 1) Fever ≥ 37.8°C (tympanic) 2) IL-6 in serum ≥ 25 pg/mL (in the absence of a previous dose of prednisone or equivalent> 1 mg / kg) or PCR> 5mg/dL 3) Lymphocytes <600 cells/mm3 4) Ferritin> 300 µg/L that doubles in 24 hours 5) Ferritin> 600 µg/L in the first determination and LDH> 250 U/L 6) D-dimer (> 1 mg/L) d. Informed verbal consent or requested under urgent conditions, documented in the electronic medical record. Exclusion criteria a. Patients who require mechanical ventilation at the time of inclusion. b. AST / ALT values > 5 folds the ULN. c. Absolute neutrophil count below 500 cells/mm3 d. Absolute platelet count below 50,000 cells/mm3 e. Documented sepsis or high suspicion of superimposed infection by pathogens other than COVID-19. f. Presence of comorbidities that can likely lead to an unfavourable result according to clinical judgment. g. Complicated diverticulitis or intestinal perforation. h. Current skin infection (eg, uncontrolled dermopiodermitis). i. Immunosuppressive anti-rejection therapy. j. Pregnancy or lactation. k. Previous treatment with tocilizumab or sarilumab. l. Patients participating in another clinical trial for SARS-CoV-2 infection. m. Patients with known hypersensitivity or contraindication to sarilumab or excipients. INTERVENTION AND COMPARATOR: The intervention group, sarilumab plus standard of care, will receive 400 mg single dose treatment with Sarilumab (Kevzara), 2 subcutaneous injections 200mg each in a pre-filled syringe. Treatment with drugs or procedures in routine clinical practice that the clinician responsible for the patient deems necessary is allowed. The control group will receive drugs or procedures in routine clinical practice according to the best standard of care as per local protocol. MAIN OUTCOMES: Primary Outcome Measures 1. Mean change in clinical status assessment using the 7-point ordinal scale at day 7 after randomisation compared to baseline (Score ranges 1-7) 1. Death; 2. Hospitalised, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalised, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalised, requiring supplemental oxygen; 5. Hospitalised, not requiring supplemental oxygen - but in need of ongoing medical care (COVID-19 related or otherwise) 6. Hospitalised, not requiring supplemental oxygen - no longer requires ongoing medical care (independent) 7. Not hospitalised 2. Duration of hospitalisation: Days from the date of enrolment to the date of discharge 3. Number of deaths at the end of study RANDOMISATION: Randomisation to treatment arms sarilumab plus standard of care or standard of care in a 2:1 ratio will be performed by the Clinical Research and Clinical Trials Unit (CRCTU) at the Hospital using a table of random numbers, an internet-based randomisation tool. After checking that all inclusion criteria are met and none of the exclusion criteria, CRCTU will communicate the recruiting investigator the assigned treatment. BLINDING (MASKING): This study is unblinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 30 patients treated by COVID-19 infection who require hospitalisation: 20 will receive sarilumab plus Standard of Care and 10 will receive Standard of Care. TRIAL STATUS: The Protocol version number is 2, as of 6th April 2020, with amendment 1, as of 7th May 2020. The recruitment is ongoing. Recruitment started on April 13th 2020 and is anticipated to be completed by November 2020. TRIAL REGISTRATION: This trial was first registered in the European Union Clinical Trials Register on 4 April 2020, EudraCT Number 2020-001634-36 . Then, posted on ClinicalTrials.gov on 22 April 2020, Identifier: NCT04357808 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the International Council Harmonization guidelines: https://www.ich.org/page/efficacy-guidelines .


Assuntos
Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Admissão do Paciente , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Esquema de Medicação , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudo de Prova de Conceito , Ensaios Clínicos Controlados Aleatórios como Assunto , Espanha , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
J UOEH ; 42(3): 261-266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879190

RESUMO

Radiation recall pneumonitis is a phenomenon in which a recall-triggering drug induces an acute inflammatory reaction in the lungs, corresponding to a previously irradiated area. Radiation recall reactions have been reported to occur following treatments with various cytotoxic anticancer agents and molecular-targeting drugs; however, only a few reports have described immune checkpoint inhibitor-induced radiation recall pneumonitis. We report a case of radiation recall pneumonitis induced by pembrolizumab in a patient with the postoperative local recurrence of non-small cell lung cancer. This case demonstrated that pembrolizumab might cause severe radiation recall pneumonitis, even after typical radiation pneumonitis has been resolved.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Doenças Assintomáticas , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Pneumonite por Radiação/etiologia , Radioterapia/efeitos adversos , Terapia Combinada , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia
8.
N Engl J Med ; 383(14): 1317-1327, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865373

RESUMO

BACKGROUND: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Criança , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Masculino , Resultado do Tratamento
9.
N Engl J Med ; 383(14): 1328-1339, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997907

RESUMO

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida
10.
Ann Hematol ; 99(11): 2463-2475, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32964342

RESUMO

TAFRO syndrome is a newly recognized disease entity characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The objective of this study was to investigate the effectiveness of tocilizumab, an anti-interleukin-6 receptor antibody, in patients with TAFRO syndrome. We performed a systematic literature review from inception to July 5, 2020, for articles reporting tocilizumab administration for the treatment of TAFRO syndrome. We identified 31 patients with TAFRO syndrome treated with tocilizumab. The mean age was 49.8 years, and 61.3% of the patients were male. The mean observation period was 12.6 months. Tocilizumab was used at the standard intravenous dose (8 mg/kg) weekly or every 2 weeks in combination with other immunosuppressive drugs, such as glucocorticoids, rituximab, cyclosporine, or cyclophosphamide, in most of the patients. Eighteen patients (58.1%) received tocilizumab as a first-line treatment, while it was a second-line or a third-line treatment for 13 patients with insufficient responses to the prior treatments. Sixteen patients (51.6%) obtained complete response to tocilizumab treatment, whereas 15 patients showed only partial or no response. Detailed factors of ineffectiveness included persistent thrombocytopenia (n = 7), persistent anasarca (n = 5), persistent renal dysfunction (n = 2), and persistent fever (n = 2). A total of four patients (12.9%) succumbed to the disease, while the remaining twenty-seven patients survived. Two patients achieved drug-free remission at last visit, and disease remission was maintained with tocilizumab monotherapy in five patients. No new safety signal was reported. Tocilizumab was effective in ~ 50% of the patients, suggesting it could serve as a treatment choice for TAFRO syndrome. Poor clinical response to tocilizumab observed in other patients highlights the need for the additional therapeutic treatment options.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Trials ; 21(1): 794, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938496

RESUMO

OBJECTIVES: In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. TRIAL DESIGN: A phase two multi-center randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h: CRP, LDH, serum ferritin, lymphopenia, or d-dimer. EXCLUSION CRITERIA: high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. MAIN OUTCOMES: Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. RANDOMIZATION: Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 1:1 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. BLINDING (MASKING): All study drugs will be administered as open label. No blinding methods will be used in this trial. NUMBERS TO BE RANDOMISED (SIMPLE SIZE): The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). TRIAL STATUS: Protocol Code: SARTRE Protocol Date: May 05th 2020. Version: 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment: August, 2020 End of recruitment: May, 2021 TRIAL REGISTRATION: Identifier: EudraCT Number: 2020-002037-15 ; Registration date: 26 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Anticorpos Monoclonais Humanizados , Betacoronavirus , Infecções por Coronavirus , Síndrome da Liberação de Citocina/prevenção & controle , Pandemias , Pneumonia Viral , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Humanos , Masculino , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etiologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Interleucina-6/antagonistas & inibidores , Resultado do Tratamento
12.
Anticancer Res ; 40(9): 5229-5235, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878811

RESUMO

BACKGROUND/AIM: The prolactin receptor (PRLR) is implicated in the tumorigenesis of breast and prostate cancers where it drives cell proliferation, survival, and migration. LFA102 is a humanized monoclonal antibody against PRLR with promising preclinical antitumor activity. To determine the maximum tolerated dose or a recommended dose, and to delineate the pharmacokinetic profile of LFA102 in Japanese patients, we conducted a phase I study. PATIENTS AND METHODS: LFA102 was intravenously infused every 4 weeks to patients with advanced breast or castration-resistant prostate cancer, and the dose increased from 3 to 40 mg/kg. RESULTS: Fourteen patients were treated, and toxicities were reported in 9 (64%) patients. They were all grade 1 or 2, and the most frequently observed toxicity was nausea (3 patients, 21%). No dose-limiting toxicities were observed. LFA102 did not show antitumor activity as a single agent. CONCLUSION: Treatment with LFA102 was well tolerated.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias de Próstata Resistentes à Castração/etiologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Resultado do Tratamento
13.
Anticancer Res ; 40(9): 5245-5254, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878813

RESUMO

BACKGROUND/AIM: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients. PATIENTS AND METHODS: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS). RESULTS: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007). CONCLUSION: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Índice de Massa Corporal , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Melanoma/complicações , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/etiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Sarcopenia/complicações , Tomografia Computadorizada por Raios X , Adulto Jovem
14.
N Engl J Med ; 383(12): 1117-1128, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32937045

RESUMO

BACKGROUND: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Azatioprina/uso terapêutico , Creatinina/urina , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Imunossupressores/efeitos adversos , Infusões Intravenosas , Análise de Intenção de Tratamento , Nefrite Lúpica/mortalidade , Masculino , Ácido Micofenólico/uso terapêutico , Indução de Remissão
15.
Lancet Oncol ; 21(10): 1353-1365, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32919526

RESUMO

BACKGROUND: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. METHODS: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. FINDINGS: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. INTERPRETATION: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias/terapia , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Neoplasias/patologia , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Análise de Sobrevida
16.
Int Heart J ; 61(5): 1070-1074, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921673

RESUMO

We report a case of lethal myocarditis and myositis after pembrolizumab treatment for advanced upper urinary tract urothelial carcinoma. A 69-year-old man underwent pembrolizumab therapy as a second-line treatment. He had myalgia and a slightly elevated creatinine kinase (CK) on the day of the second administration of pembrolizumab. Five days later, the patient was admitted with severe fatigue and an abnormal gait. Physical examination revealed reduced muscle reflexes and proximal muscle weakness. An electrocardiogram (ECG) demonstrated a wide QRS complex ventricular rhythm. A marked elevation of cardiac enzymes, including CK, myoglobin, and cardiac troponin I, was detected. Myocardial biopsy revealed inflammatory cell infiltration and the partial impairment of myocardial tissue. The electromyogram was normal, but inflammation in myofibers was noted in a muscle biopsy. Myocarditis and myositis as immune-related adverse events (irAEs) were suspected, and the patient began intravenous steroid therapy and plasma exchange. However, the patient underwent cardiac arrest three days after admission and began extracorporeal membrane oxygenation and intra-aortic balloon pumping therapy. Despite steroid pulse therapy, the patient demonstrated no sign of improvement and subsequently died 17 days after admission. Immune-mediated myocarditis is a rare but fatal irAE of an immune checkpoint inhibitor (ICI). The present case suggests that myositis precedes myocarditis. Therefore, if myositis is suspected, subsequent myocarditis may need attention. In conclusion, we found that myositis and myocarditis developed in a patient with advanced urothelial carcinoma after pembrolizumab treatment. A routine follow-up of CK and cardiac troponin I, as well as an ECG, should be performed to identify any possible ICI-induced myocarditis and myositis quickly.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Miocardite/induzido quimicamente , Miosite/induzido quimicamente , Idoso , Carcinoma de Células de Transição/secundário , Creatina Quinase/sangue , Creatina Quinase Forma MB/sangue , Ecocardiografia , Eletromiografia , Oxigenação por Membrana Extracorpórea , Evolução Fatal , Glucocorticoides/uso terapêutico , Parada Cardíaca , Humanos , Balão Intra-Aórtico , Pelve Renal , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Músculo Esquelético/patologia , Miocardite/sangue , Miocardite/diagnóstico por imagem , Miocardite/patologia , Miocárdio/patologia , Mioglobina/sangue , Miosite/sangue , Miosite/patologia , Miosite/fisiopatologia , Troca Plasmática , Troponina I/sangue
17.
Cochrane Database Syst Rev ; 9: CD008333, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32990324

RESUMO

BACKGROUND: Anti-neutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are a group of rare auto-inflammatory diseases that affects mainly small vessels. AAV includes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Anti-cytokine targeted therapy uses biological agents capable of specifically targeting and neutralising cytokine mediators of the inflammatory response. OBJECTIVES: To assess the benefits and harms of anti-cytokine targeted therapy for adults with AAV. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (2019, Issue 7), MEDLINE and Embase up to 16 August 2019. We also examined reference lists of articles, clinical trial registries, websites of regulatory agencies and contacted manufacturers. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials of targeted anti-cytokine therapy in adults (18 years or older) with AAV compared with placebo, standard therapy or another modality and anti-cytokine therapy of different type or dose. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included four RCTs with a total of 440 participants (mean age 48 to 56 years). We analysed the studies in three groups: 1) mepolizumab (300 mg; three separate injections every four weeks for 52 weeks) versus placebo in participants with relapsing or refractory EGPA; 2) belimumab (10 mg/kg on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised) or etanercept (25 mg twice a week) with standard therapy (median 25 months) versus placebo with standard therapy (median 19 months) in participants with GPA/MPA; and 3) infliximab (3 mg/kg on days 1 and 14, before the response assessment on day 42) versus rituximab (0.375g/m2 on days 1, 8, 15 and 22) in participants with refractory GPA for up to 12 months. None of the studies were assessed as low risk of bias in all domains: one study did not report randomisation or blinding methods clearly. Three studies were at high risk and one study was at unclear risk of bias for selective outcome reporting. One trial with 136 participants with relapsing or refractory EGPA compared mepolizumab with placebo during 52 weeks of follow-up and observed one death in the mepolizumab group (1/68, 1.5%) and none in the placebo group (0/68, 0%) (Peto odds ratio (OR) 7.39, 95% confidence interval (CI) 0.15 to 372.38; low-certainty evidence). Low-certainty evidence suggests that more participants in the mepolizumab group had ≥ 24 weeks of accrued remission over 52 weeks compared to placebo (27.9% versus 2.9%; risk ratio (RR) 9.5, 95% CI 2.30 to 39.21), and durable remission within the first 24 weeks sustained until week 52 (19.1% mepolizumab versus 1.5% placebo; RR 13.0, 95% CI 1.75 to 96.63; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% Cl 4 to 13). Mepolizumab probably decreases risk of relapse (55.8% versus 82.4%; RR 0.68, 95% CI 0.53 to 0.86; NNTB 4, 95% CI 3 to 9; moderate-certainty evidence). There was low-certainty evidence regarding similar frequency of adverse events (AEs): total AEs (96.9% versus 94.1%; RR 1.03, 95% CI 0.96 to 1.11), serious AEs (17.7% versus 26.5%; RR 0.67, 95% CI 0.35 to 1.28) and withdrawals due to AEs (2.9% versus 1.5%; RR 2.00, 95% CI 0.19 to 21.54). Disease flares were not measured. Based on two trials with different follow-up periods (mean of 27 months for etanercept study; up to four years for belimumab study) including people with GPA (n = 263) and a small group of participants with MPA (n = 22) analysed together, we found low-certainty evidence suggesting that adding an active drug (etanercept or belimumab) to standard therapy does not increase or reduce mortality (3.4% versus 1.4%; Peto OR 2.45, 95% CI 0.55 to 10.97). Etanercept may have little or no effect on remission (92.3% versus 89.5%; RR 0.97, 95% CI 0.89 to 1.07), durable remission (70% versus 75.3%; RR 0.93, 95% CI 0.77 to 1.11; low-certainty evidence) and disease flares (56% versus 57.1%; RR 0.98, 95% CI 0.76 to 1.27; moderate-certainty evidence). Low-certainty evidence suggests that belimumab does not increase or reduce major relapse (1.9% versus 0%; RR 2.94, 95% CI 0.12 to 70.67) or any AE (92.5% versus 82.7%; RR 1.12, 95% CI 0.97 to 1.29). Low-certainty evidence suggests a similar frequency of serious or severe AEs (47.6% versus 47.6%; RR 1.00, 95% CI 0.80 to 1.27), but more frequent withdrawals due to AEs in the active drug group (11.2%) compared to the placebo group (4.2%), RR 2.66, 95% CI 1.07 to 6.59). One trial involving 17 participants with refractory GPA compared infliximab versus rituximab added to steroids and cytotoxic agents for 12 months. One participant died in each group (Peto OR 0.88, 95% CI, 0.05 to 15.51; 11% versus 12.5%). We have very low-certainty evidence for remission (22% versus 50%, RR 0.44, 95% Cl 0.11 to 1.81) and durable remission (11% versus 50%, RR 0.22, 95% CI 0.03 to 1.60), any severe AE (22.3% versus 12.5%; RR 1.78, 95% CI 0.2 to 16.1) and withdrawals due to AEs (0% versus 0%; RR 2.70, 95% CI 0.13 to 58.24). Disease flare/relapse and the frequency of any AE were not reported. AUTHORS' CONCLUSIONS: We found four studies but concerns about risk of bias and small sample sizes preclude firm conclusions. We found moderate-certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably decreases disease relapse and low-certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of disease remission. There were similar frequencies of total and serious AEs in both groups, but the study was too small to reliably assess these outcomes. Mepolizumab may result in little to no difference in mortality. However, there were very few events. In participants with GPA (and a small subgroup of participants with MPA), etanercept or belimumab may increase the probability of withdrawal due to AEs and may have little to no impact on serious AEs. Etanercept may have little or no impact on durable remission and probably does not reduce disease flare.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Imunossupressores/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome de Churg-Strauss/tratamento farmacológico , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Imunossupressores/efeitos adversos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Poliangiite Microscópica/tratamento farmacológico , Pessoa de Meia-Idade , Números Necessários para Tratar , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Prevenção Secundária , Esteroides/administração & dosagem
18.
N Engl J Med ; 383(6): 546-557, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32757523

RESUMO

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Crotonatos/uso terapêutico , Injeções Subcutâneas/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Toluidinas/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Linfócitos B , Encéfalo/patologia , Crotonatos/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/patologia , Linfócitos T , Toluidinas/efeitos adversos
19.
Nat Commun ; 11(1): 3924, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764665

RESUMO

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Monócitos/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Biologia Computacional , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/sangue , Humanos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-6/imunologia , Análise de Célula Única/métodos
20.
Artigo em Inglês | MEDLINE | ID: mdl-32816957

RESUMO

Tocilizumab, a monoclonal antibody against interleukin-6, has been used to treat cytokine release syndrome (CRS) in a subset of patients with severe COVID-19 disease. Acute ulcerative bowel disease has been only rarely documented in patients treated for rheumatological conditions. The gastrointestinal side effects seen when used in the context of COVID-19 are unknown. We present a case of COVID-19 CRS in which acute terminal ileum and perforated caecal ulceration evolved after tocilizumab exposure. We raise awareness of a possible causal relationship between even a single dose of tocilizumab and gut ulceration in patients with COVID-19. Any such drug enteropathy relationship requires watchful monitoring during upcoming trials of tocilizumab in patients with COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus , Colite Ulcerativa/induzido quimicamente , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Colectomia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/cirurgia , Infecções por Coronavirus/epidemiologia , Humanos , Masculino , Pandemias , Pneumonia Viral/epidemiologia
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