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1.
BMC Infect Dis ; 20(1): 753, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054715

RESUMO

BACKGROUND: Safety of live vaccines in patients treated with immunosuppressive therapies is not well known, resulting in contradictory vaccination recommendations. We describe here the first case of vaccine-associated measles in a patient on natalizumab treatment. CASE PRESENTATION: A young female patient with relapsing-remitting multiple sclerosis on natalizumab treatment received the live attenuated measles, mumps, and rubella vaccine in preparation for a change in her treatment in favour of fingolimod, with established immunosuppressive qualities. Seven days after receiving the vaccine, our patient experienced diffuse muscle pain, fatigue, and thereafter developed a fever and then an erythematous maculopapular rash, compatible with vaccine associated measles. This was later confirmed by a positive measles RT-PCR throat swab. The patient's symptoms resolved without any sequelae. CONCLUSION: In this case report we review the immunosuppressive qualities of natalizumab and the evidence in favour and against live vaccines in patients on this treatment. Our findings reveal the insufficient understanding of the immunosuppressive effects of new immunomodulators, and thus of the safety of live vaccines in patients on such medications. While this case triggers precaution, there is insufficient evidence to conclude that natalizumab treatment could favor the onset of vaccine-associated measles.


Assuntos
Vacina contra Sarampo/efeitos adversos , Vacina contra Sarampo-Caxumba-Rubéola/uso terapêutico , Sarampo/etiologia , Natalizumab/uso terapêutico , Adulto , Exantema/induzido quimicamente , Feminino , Febre/etiologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Sarampo/diagnóstico , Vacina contra Sarampo/uso terapêutico , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/imunologia , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico
3.
Medicine (Baltimore) ; 99(31): e21490, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756179

RESUMO

BACKGROUND: Whether the combination of gefitinib and chemotherapy is beneficial for advanced non-small cell lung cancer (NSCLC) remains controversial. This study aimed to summarize the currently available evidence and compare the efficacy and safety of gefitinib combined with chemotherapy versus chemotherapy alone for treating advanced NSCLC. METHODS: Literature on comparing the effects of gefitinib combined with chemotherapy and chemotherapy alone in treating NSCLC was retrieved from the PubMed, EMBASE and Cochrane Database. The primary outcome measures included progression-free survival (PFS) and overall survival (OS). Revman 5.3 was used for data processing. RESULTS: Seven randomized controlled trials were included, involving a total of 1418 patients. There appeared a significant improvement in PFS (hazard ratio (HR) = 0.60 [95% CI 0.43, 0.82], P = .001) after treatment with gefitinib combined with chemotherapy when compared with chemotherapy alone. The subgroup analysis showed a significant advantage of sequential administration (HR = 0.67 [95% CI 0.57, 0.79], P < .00001). There was no significant improvement in OS (HR = 0.92 [95% CI 0.71, 1.20], P = .54), and no significant improvement in overall response rate (ORR) (HR = 0.98 [95% CI 0.67, 1.44], P = .93). The risks of rash and diarrhea (odds ratios) were higher in gefitinib combined with chemotherapy group when compared with chemotherapy alone, and there were significant differences on grade 3/4 rash and thrombocytopenia between 2 groups. CONCLUSION: Gefitinib combined with chemotherapy is superior to chemotherapy alone in PFS, sequential administration prolongs the patients' PFS, however, a survival advantage is not shown in OS or ORR. Gefitinib combined with chemotherapy aggravates rash, diarrhea and thrombocytopenia.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Exantema/induzido quimicamente , Feminino , Gefitinibe/efeitos adversos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
5.
Dermatol Online J ; 26(6)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32815686

RESUMO

Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare delayed drug reaction that often occurs 2-6 weeks after initiation of therapy and may develop into a life-threatening systemic reaction. Besides immediate discontinuation of the suspected inciting drug, initiation of high dose systemic corticosteroids has long been the mainstay of treatment for severe cases. Nevertheless, significant drawbacks associated with systemic corticosteroid therapy, such as the requirement of a long tapering period post resolution and extensive adverse side effects profile, have motivated clinicians to seek alternative treatment options. Over the past decade, an undisputed increasing number of favorable case reports has highlighted cyclosporine as an emerging, safe, and effective alternative despite inconsistent dosing regimens reported. Herein, we report a severe case of vancomycin-induced DRESS syndrome in which the patient failed initial intervention with cyclosporine and needed rescue with methylprednisolone. To the best of our knowledge, this constitutes the first unsuccessful report of cyclosporine treatment for DRESS syndrome.


Assuntos
Ciclosporina/uso terapêutico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Vancomicina/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Síndrome de Hipersensibilidade a Medicamentos/patologia , Resistência a Medicamentos , Eosinofilia/induzido quimicamente , Eosinofilia/patologia , Exantema/induzido quimicamente , Feminino , Antebraço/patologia , Humanos
6.
PLoS One ; 15(8): e0236264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750060

RESUMO

BACKGROUND: Extensively drug-resistant tuberculosis (XDR TB) is a very serious form of tuberculosis that is burdened with a heavy mortality toll, especially before the advent of new TB drugs. The Democratic Republic of the Congo (DRC) is among the countries most affected by this new epidemic. METHODS: A retrospective analysis was performed of the records of all patients with pre- and extensively drug-resistant tuberculosis hospitalized from January 1, 2015 to December 31, 2017 and monitored for at least 6 months to one year after the end of their treatment in Kinshasa; an individualized therapeutic regimen with bedaquiline for 20 months was built for each patient. The adverse effects were systematically monitored. RESULTS: Of the 40 laboratory-confirmed patients, 32 (80%) patients started treatment, including 29 preXRB and 3 XDR TB patients. In the eligible group, 3 patients (9.4%) had HIV-TB coinfections. The therapeutic success rate was 53.2%, and the mortality rate was 46.8% (15/32); there were no relapses, failures or losses to follow-up. All coinfected HIV-TB patients died during treatment. The cumulative patient survival rate was 62.5% at 3 months, 53.1% at 6 months and 53.1% at 20 months. The most common adverse events were vomiting, Skin rash, anemia and peripheral neuropathy. CONCLUSION: The new anti-tuberculosis drugs are a real hope for the management of Drug Resistant tuberculosis patient and other new therapeutic combinations may improve favorable outcomes.


Assuntos
Antituberculosos/administração & dosagem , Diarilquinolinas/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adolescente , Adulto , Idoso , Anemia/induzido quimicamente , Anemia/epidemiologia , Antituberculosos/efeitos adversos , Efeitos Psicossociais da Doença , República Democrática do Congo/epidemiologia , Diarilquinolinas/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Exantema/induzido quimicamente , Exantema/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/epidemiologia , Adulto Jovem
7.
Travel Med Infect Dis ; 36: 101812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645478

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is currently being examined for COVID-19. No previous meta-analysis has evaluated its side effects versus placebo. We conducted this meta-analysis to compare the safety of HCQ versus placebo. METHODS: Two authors independently searched PubMed and EMBASE databases for randomized controlled trials (RCTs) of adults comparing the adverse events (AEs) of HCQ versus placebo for any indication. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were calculated based on random-effects models. The heterogeneity (I2) was assessed using Cochran's Q test. RESULTS: Nine RCTs (eight were double-blind) with a total of 916 patients were included. HCQ caused significantly more skin pigmentation than placebo (Peto OR, 4.64; 95% CI, 1.13 to 19.00; P-value = 0.033; I2 = 0%). The increase in other AEs did not reach statistical significance: rash (Peto OR, 1.11; 95% CI, 0.3 to 3.77; P-value = 0.03; I2 = 0%); gastrointestinal AEs (Peto OR, 1.43; 95% CI, 0.55 to 3.72; P-value = 0.46; I2 = 15.17%); headache (Peto OR, 1.94; 95% CI, 0.65 to 5.78; P-value = 0.23; I2 = 9.99%); dizziness (Peto OR, 1.32; 95% CI, 0.49 to 3.52; P-value = 0.58; I2 = 0%); fatigue (Peto OR, 2.13; 95% CI, 0.76 to 5.98; P-value = 0.15; I2 = 0%); and visual AEs (Peto OR, 1.61; 95% CI, 0.76 to 3.41; P-value = 0.22; I2 = 0%). Cardiac toxicity was not reported. CONCLUSIONS: This meta-analysis of RCTs found a significantly higher risk of skin pigmentation in HCQ users versus placebo. More data are needed to evaluate HCQ in the context of COVID-19 treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antirreumáticos/efeitos adversos , Urticária Crônica/tratamento farmacológico , Glomerulonefrite por IGA/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Hiperpigmentação/induzido quimicamente , Doenças Reumáticas/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Infecções Assintomáticas , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Tontura/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Cochrane Database Syst Rev ; 7: CD007783, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609387

RESUMO

BACKGROUND: This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs. OBJECTIVES: To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures. SEARCH METHODS: For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. SELECTION CRITERIA: Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing. MAIN RESULTS: We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study. Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence). The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74). AUTHORS' CONCLUSIONS: This review provides insufficient information to inform clinical practice. Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Tônico-Clônica/tratamento farmacológico , Lamotrigina/uso terapêutico , Anticonvulsivantes/efeitos adversos , Quimioterapia Adjuvante/métodos , Tontura/induzido quimicamente , Erupção por Droga/etiologia , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Humanos , Lamotrigina/efeitos adversos , Náusea/induzido quimicamente , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sonolência
11.
Adv Exp Med Biol ; 1244: 235-246, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301018

RESUMO

Due to the novelty of immune checkpoint inhibitors, their cutaneous adverse events (AEs) have only been recently characterized. This, along with the substantial rate of cutaneous reactions, has left many clinicians without sufficient familiarity to diagnose and treat cutaneous AEs. Pruritus and rash are among the top five immune-related AEs reported in clinical trials for this class of therapy. Incidence varies between 35 and 50% for cutaneous AEs among the eight FDA-approved drugs. Although only 2% are reported as grade 3 or 4 events, the impact on quality of life can be significant for these patients and is best described and most severe in ipilimumab trials. Of ipilimumab patients, 43.5% have a cutaneous AE and, at our institution, 20% of them had a dose interruption as a result. This means potentially 9% of patients have dose interruption of ipilimumab because of their cutaneous AEs. In the following chapter, we review the categories of these drugs, common cutaneous effects, their grading, and management options.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Exantema/induzido quimicamente , Imunoterapia/efeitos adversos , Ipilimumab/efeitos adversos , Neoplasias/terapia , Prurido/induzido quimicamente , Exantema/diagnóstico , Exantema/terapia , Humanos , Neoplasias/imunologia , Prurido/diagnóstico , Prurido/terapia , Qualidade de Vida
13.
Artigo em Inglês | MEDLINE | ID: mdl-32178607

RESUMO

This report summarises Australian spontaneous surveillance data for adverse events following immunisation (AEFI) for 2018 reported to the Therapeutic Goods Administration and describes reporting trends over the 19-year period 1 January 2000 to 31 December 2018. There were 4221 AEFI records for vaccines administered in 2018, an annual AEFI reporting rate of 16.9 per 100,000 population. There was a 2.9% increase in the overall AEFI reporting rate in 2018 compared to 2017. This slight increase in reported adverse events in 2018 was likely due to new additions to the National Immunisation Program schedule, namely meningococcal ACWY vaccination for children aged 12 months, enhanced immunogenicity trivalent influenza vaccines for adults aged ≥65 years, and state- and territory-funded seasonal influenza vaccination programs for children aged 6 months to <5 years. AEFI reporting rates for most individual vaccines in 2018 were similar to 2017. The most commonly reported adverse events were injection site reaction (34%), pyrexia (15%), rash (15%), vomiting (8%), headache (6%) and pain (6%). Two deaths were reported to the TGA but no clear causal relationship with vaccination was found.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Programas de Imunização , Vacinação/efeitos adversos , Adolescente , Adulto , Idoso , Austrália/epidemiologia , Criança , Pré-Escolar , Exantema/induzido quimicamente , Febre/induzido quimicamente , Humanos , Esquemas de Imunização , Lactente , Vacinas contra Influenza , Reação no Local da Injeção , Masculino , Adulto Jovem
15.
Int J Clin Pharmacol Ther ; 58(4): 242-246, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32000885

RESUMO

OBJECTIVE: Vancomycin is a commonly used glycopeptide antibiotic due to its effectiveness in treating serious Gram-positive bacterial infections, especially methicillin-resistant Staphylococcus aureus (MRSA) infection. Pancytopenia is a rare, yet serious, complication of vancomycin. Previous isolated cases have been reported in adults but none in children. CASE REPORT: A 16-month-old boy received vancomycin for treatment of osteomyelitis caused by MRSA. During his administration of vancomycin, reversible pancytopenia, pulmonary infection, and skin rash developed, which resolved after withdrawal. CONCLUSION: This is the first known case of vancomycin causing reversible pancytopenia and skin rash in a child, suggesting that pancytopenia caused by vancomycin could complicate treatment of children, and the hypothesis that pancytopenia is an immune-mediated reaction seems to be preferable. According to drug hypersensitivity syndrome (DHS) risk assessment in 10-D assessment system, this case was at grade of no risk.


Assuntos
Antibacterianos/efeitos adversos , Exantema/induzido quimicamente , Osteomielite/tratamento farmacológico , Pancitopenia/induzido quimicamente , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/efeitos adversos , Humanos , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina , Osteomielite/complicações , Osteomielite/microbiologia , Infecções Estafilocócicas/complicações
17.
BMC Cancer ; 20(1): 155, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093649

RESUMO

BACKGROUND: Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. METHODS: This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0-1, 2) and age (≤65 years, > 65 years). RESULTS: Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. CONCLUSIONS: Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Exantema/induzido quimicamente , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Cloridrato de Erlotinib/administração & dosagem , Exantema/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Taxa de Sobrevida
18.
BMC Cancer ; 20(1): 157, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32103736

RESUMO

BACKGROUND: Rash is one of the most common severe adverse events associated with use of vemurafenib for the treatment of melanoma, either as monotherapy or in combination with cobimetinib. The study aimed to identify pre-treatment patient characteristics predictive of developing severe rash with vemurafenib therapy. METHODS: This was a secondary pooled analysis of individual patient data from the BRIM-2, BRIM-3 and coBRIM clinical trials, including all patients treated with vemurafenib alone and vemurafenib plus cobimetinib. Patient age, sex, performance status, body weight, body mass index, liver function markers and estimated glomerular filtration rate were assessed for association with development of severe (grade 3 or 4) rash using logistic regression. RESULTS: Of 962 patients treated with vemurafenib, 150 (16%) patients experienced severe rash. Female sex was identified as a significant risk factor for severe rash development (P < 0.001), having a two-fold increased risk compared to males (22% vs 11%, odds ratio [OR] 2.17; 95% CI 1.52 to 3.09). Low body weight was also associated with increased risk of severe rash (P = 0.002), but this association was not significant after adjustment for sex. The association between sex and risk of severe rash was consistent across clinical trials and treatments (vemurafenib monotherapy, vemurafenib plus cobimetinib). CONCLUSION: Females had approximately two-fold increased risk of developing severe rash compared to males in clinical trials of vemurafenib alone or in combination with cobimetinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Exantema/induzido quimicamente , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Austrália/epidemiologia , Azetidinas/administração & dosagem , Exantema/epidemiologia , Exantema/patologia , Feminino , Humanos , Incidência , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Piperidinas/administração & dosagem , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/patologia , Vemurafenib/administração & dosagem
19.
J Immunother Cancer ; 8(1)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32066648

RESUMO

BACKGROUND: Immune checkpoint inhibitors such as nivolumab and targeted BRAF inhibitors have dramatically altered the treatment outcomes of metastatic melanoma over the past few years. Skin toxicity is the most common adverse event (AE) related to the commonly used BRAF inhibitor vemurafenib, affecting more than 90% of patients. Vemurafenib-related severe AEs with early onset are reported in patients who were previously treated with anti-programmed cell death-1 (anti PD-1) antibodies. A prolonged administration of systemic steroids is the first-line treatment of severe or life-threatening AEs. We report the case of a woman suffering from vemurafenib-related severe, rapidly worsening Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, resolved in a few hours after single-dose administration of a combination of TNF-α antagonist infliximab with interleukin (IL)-6 receptor antagonist tocilizumab. CASE PRESENTATION: A 41-year-old woman treated with single-agent nivolumab presented with a melanoma progression. Biopsy samples were revised, revealing a BRAF V600E mutation. The patient was started on vemurafenib and cobimetinib treatment only 10 days after the last administration of nivolumab. On the third day of anti-BRAF therapy, profound lymphopenia was detected, and maculopapular eruption appeared afterward. Subsequently, the clinical conditions deteriorated further, and the woman was admitted on an emergency basis with high fever, respiratory and cardiocirculatory failure, diffuse rash, generalized edema, and lymphadenopathy. Diagnosis of DRESS syndrome with overexpressed capillary leakage was made. A single dose of tocilizumab was administered with an improvement of cardiocirculatory and renal function in a few hours. Because of worsening of liver function, skin lesions and mucositis, a single dose of infliximab was prescribed, and dramatic improvement was noted over the next 24 hours. Dabrafenib and trametinib were initiated, and coinciding with washout of infliximab from the patient's blood, the drug toxicity recurred. CONCLUSION: Anti-IL-6 and anti-TNF-α target treatment of very severe AEs may afford an immediate resolution of potentially life-threatening symptoms and reduce the duration and the costs of hospitalization. Maintenance of therapeutic infliximab blood concentrations permits an early switch to dabrafenib after vemurafenib-related AEs.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Eosinofilia/tratamento farmacológico , Exantema/tratamento farmacológico , Infliximab/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Eosinofilia/induzido quimicamente , Exantema/induzido quimicamente , Feminino , Humanos , Melanoma/imunologia , Nivolumabe/administração & dosagem , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Vemurafenib/administração & dosagem
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