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

Abstract

IntroductionThe 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.MethodsMILES 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.ResultsIn the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±seFEV1slope −17±3versus−3±3 mL·month−1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (−17±3versus−1±2 mL·month−1; p<0.0001) and post-menopausal patients (−3±3versus6±3 mL·month−1; p=0.04) exhibited a beneficial response in mean±seFEV1slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1did 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−1identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus.ConclusionsIn LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.

Lymphangioleiomyomatosis

“…Mladší, premenopauzální ženy mají obvykle rychlejší pokles plicních funkčních parametrů nežli ženy starší, postmenopauzální [6,7]. Předpokládá se, že pacienti s TS/ LAM mají ve srovnání se S/ LAM mírnější a méně progresivní onemocnění [52,53]. V našem souboru máme jen dvě pacientky s TS/ LAM.…”

Identification of the lymphangioleiomyomatosis cell and its uterine origin

“…LAM is usually diagnosed in women of reproductive-age, suggesting an important role for female sex hormones in disease pathogenesis . Clinical observations that the menstrual cycle influences respiratory symptoms and occurrence of pneumothorax, and that decline of lung function slows after menopause and accelerates with exogenous estrogen use and pregnancy are consistent with this concept (Cohen et al, 2009;Gupta et al, 2019;Johnson and Tattersfield, 1999;Shen et al, 1987). Lymphadenopathy caused by LAM is more prominent in the pelvis and retroperitoneum than in the nodes in upper abdomen, thorax and mediastinum, suggesting a pelvic source for the neoplasm (Glasgow et al, 2008;Tobino et al, 2015).…”

“…The allele frequency of TSC1 or TSC2 mutations within LAM lesions range from 4% to 60%, with average less than 20% (Badri et al, 2013), supporting the concept that recruited stromal cells, rather than mutation-bearing LAM cells, dominate within the lesions (Badri et al, 2013;Clements et al, 2015;Johnson and Tattersfield, 1999). The mTOR inhibitor, Sirolimus, is an FDA-approved suppressive therapy that stabilizes lung function in most LAM patients (Gupta et al, 2019;McCormack et al, 2011); however, the drug does not eliminate LAM cells and can be associated with significant side-effects (McCormack et al, 2011). There is therefore an urgent need to develop new molecular targets and treatments for LAM.…”

Multiple cutaneous nodules in a 7-month-old boy

“…Skin lesions include hypomelanotic macules (90% of patients), facial angiofibromas (75% of patients), fibrous cephalic plaques (25% of patients) and shagreen patches (> 50% of patients) (1). Study has reported that the use of sirolimus on specific TSC manifestations (2)(3)(4).…”