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.

FIGURE 1

Effect of a) menopause and b) race on forced expiratory volume in 1 s (FEV₁) response. Pre-MP: pre-menopausal; post-MP: post-menopausal. a) Mean±se FEV₁ response by menopausal status. In the overall cohort, sirolimus stabilised FEV₁ decline. In the placebo group, pre-MP females exhibited a significantly faster rate of decline of FEV₁ compared with post-MP females. Both the pre-MP and post-MP females exhibited a beneficial response to treatment with sirolimus, with pre-MP females experiencing a slowing in the rate of decline and post-MP females trending towards improvement. b) Mean±se FEV₁ response by race. In the overall cohort, sirolimus stabilised FEV₁ decline. There was no difference in the rate of decline of FEV₁ in the Asian and Caucasian patients enrolled in MILES, and both subgroups responded to treatment with sirolimus.

FIGURE 2

Effect of a) menopause and b) race on forced vital capacity (FVC) response. Pre-MP: pre-menopausal; post-MP: post-menopausal. a) Mean±se FVC response by menopausal status. In the overall cohort, sirolimus stabilised FVC decline. In the placebo group, pre-MP females had a significantly faster rate of decline in FVC compared with post-MP females. Both the pre-MP and post-MP females had a beneficial response to treatment with sirolimus. b) Mean±se FVC response by race. The rate of decline in FVC was similar in the placebo groups of both the Asian and Caucasian patients. The difference between placebo and sirolimus groups in FVC slope was statistically significant in the Caucasian patients, and trended towards significance in the Asian patients.

FIGURE 3

Effect of a) menopause and b) race on serum vascular endothelial growth factor (VEGF)-D response. Pre-MP: pre-menopausal; post-MP: post-menopausal. a) Mean±se change in serum VEGF-D levels among pre-MP and post-MP patients. In the overall cohort, serum VEGF-D levels were stable over time in the placebo group and declined in the sirolimus group. This was also true in the pre-MP patients, but the between-group difference in post-MP patients did not achieve significance, likely due to the small patient numbers. b) Mean±se change in serum VEGF-D levels among Asian and Caucasian patients. Both the Asian and Caucasian subjects exhibited a significant decline in serum VEGF-D levels following treatment with sirolimus.

FIGURE 4

Mean±se change from baseline to 12 months in forced expiratory volume in 1 s (FEV₁) response in the MILES trial placebo and sirolimus groups, stratified by a) vascular endothelial growth factor (VEGF)-D levels and b) menopausal status. Pre-MP: pre-menopausal; post-MP: post-menopausal. a) Baseline VEGF-D >600 or ⩽600 pg·mL⁻¹. Lung function in patients with baseline serum VEGF-D ⩽600 pg·mL⁻¹ remained relatively stable throughout the 12-month monitoring period in both the placebo and sirolimus subgroups. Patients with serum VEGF-D >600 pg·mL⁻¹ exhibited a faster decline in the placebo subgroup and improved treatment response to sirolimus. b) Pre-MP versus post-MP patients. Pre-MP patients on placebo had the highest rate of decline of lung function and had an overall stabilisation of FEV₁ decline on sirolimus. Post-MP patients on placebo remained relatively stable during the 12-month monitoring period and exhibited an overall improvement in their FEV₁ following treatment with sirolimus.

FIGURE 5

Percentage change from baseline in serum vascular endothelial growth factor (VEGF)-D levels and forced expiratory volume in 1 s (FEV₁) over 12 months. The placebo group exhibited progressive decline in FEV₁ with relatively stable VEGF-D levels, whereas the sirolimus group tended to have stable FEV₁ with declining serum VEGF-D values during the 12-month treatment period.

FIGURE 6

Time course of adverse events during the first 12 months of the MILES trial. The total numbers of adverse events are shown for both the sirolimus and placebo arms. In general, there were more adverse events in the sirolimus arm compared with the placebo arm and there was a decrease in the frequency of adverse events over the course of the trial in both arms.