RESUMO
Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5â mg·day(-1) escalated to 10â mg·day(-1)) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26â weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1â s improved from baseline, with mean changes (95% confidence interval) of 10â mL (-111-132) and 114â mL (11-217), respectively; 6-min walk distance improved by 47â m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730â pg·mL(-1) to 934.5â pg·mL(-1), and 103â ng·mL(-1) to 80.5â ng·mL(-1), respectively. Adverse events were mostly grade 1-2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe.
Assuntos
Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Fator D de Crescimento do Endotélio Vascular/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Intervalos de Confiança , Relação Dose-Resposta a Droga , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Linfangioleiomiomatose/patologia , Dose Máxima Tolerável , Pessoa de Meia-Idade , Medição de Risco , Resultado do Tratamento , Fator D de Crescimento do Endotélio Vascular/sangue , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologia , Adulto JovemRESUMO
This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.
RESUMO
Pulmonary complications of alpha interferon are rare. We report two cases of lung complications in liver transplantation patients for HCV related cirrhosis. After switching from interferon alpha to pegylated interferon alpha 2b, one patient developed a BOOP (Bronchiolitis Obliterans Organizing Pneumonia) and the other severe interstitial pneumonitis. We discuss the causes of these rare pulmonary alpha-interferon induced complications and the different way to suggest that the pegylated interferon alpha 2b could be related to the risk of pulmonary toxicity of this treatment.