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Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

ABSTRACT: INTRODUCTION:The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. METHODS:MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1?s (FEV1; 51-70% versus ?50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. RESULTS:In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV1 slope -17±3 versus -3±3?mL·month-1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 versus -1±2?mL·month-1; p<0.0001) and post-menopausal patients (-3±3 versus 6±3?mL·month-1; p=0.04) exhibited a beneficial response in mean±se FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600?pg·mL-1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. CONCLUSIONS:In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.

SUBMITTER: Gupta N

PROVIDER: S-EPMC7394189 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

Gupta Nishant N Lee Hye-Seung HS Young Lisa R LR Strange Charlie C Moss Joel J Singer Lianne G LG Nakata Koh K Barker Alan F AF Chapman Jeffrey T JT Brantly Mark L ML Stocks James M JM Brown Kevin K KK Lynch Joseph P JP Goldberg Hilary J HJ Downey Gregory P GP Taveira-DaSilva Angelo M AM Krischer Jeffrey P JP Setchell Kenneth K Trapnell Bruce C BC Inoue Yoshikazu Y McCormack Francis X FX

The European respiratory journal 20190404 4

<h4>Introduction</h4>The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM.<h4>Methods</h4>MILES subjects were stratified on the basis of menopausal status (p ...[more]

PMID: 30846465

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Project description:BACKGROUND:VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. METHODS:In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. FINDINGS:We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99–2·86] vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). INTERPRETATION:Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. FUNDING:National Institutes of Health, US Department of Defense.

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Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

Publications

Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis.

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