Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis

Abstract

Background: Lymphangioleiomyomatosis is a rare disease caused by unregulated activation of mammalian target of rapamycin (mTOR) signalling pathway. Sirolimus showed efficacy in a phase 3 trial of patients with lymphangioleiomyomatosis, but the optimal dose remains unclear.

Methods: We investigated the efficacy and safety of low-dose compared with conventional-dose sirolimus. Clinical data of 39 patients with lymphangioleiomyomatosis (mean age, 34.8 years; median treatment period, 29.6 months) who received sirolimus were retrospectively reviewed. Low-dose sirolimus was defined as any dose that maintained mean blood trough levels lower than those maintained with conventional doses (5-15 ng/mL).

Results: Fifty-one percent of patients received low-dose therapy. The rate of decline in lung function decreased after treatment in the whole group (forced expiratory volume in 1 s [FEV₁], - 0.12 ± 0.47 [before] vs. 0.24 ± 0.48% predicted/month [after], p = 0.027; diffusing capacity for carbon monoxide [DLco], - 0.33 ± 0.61 vs. 0.03 ± 0.26% predicted/month, p = 0.006) compared with before treatment. In the low-dose group, the rate of decline in FEV₁ (- 0.08 ± 0.38 [before] vs. 0.19 ± 0.51% predicted/month [after], p = 0.264) and DLco (-0.13 ± 0.62 vs. 0.02 ± 0.28% predicted/month, p = 0.679) showed a numeric trend towards improvement after treatment; however, the conventional-dose group showed significant improvement in FEV₁ (- 0.26 ± 0.54 [before] vs. 0.22 ± 0.38 [after] % predicted/month, p = 0.024) and DLco (- 0.55 ± 0.58 vs. 0.04 ± 0.25% predicted/month, p = 0.002) after treatment. Adverse events (AEs) occurred in 89.7% of patients and the most common AEs was hypercholesterolaemia (43.6%), followed by stomatitis (35.9%). The occurrences of AE were similar between the low- and conventional-dose groups (85.0% vs. 94.7%, p = 0.605).

Conclusions: Low-dose sirolimus may stabilise lung function decline in lymphangioleiomyomatosis patients, but its efficacy appears to be inferior to that of conventional-dose sirolimus.

Keywords: Low dose; Lymphangioleiomyomatosis; Respiratory function tests; Sirolimus; Treatment outcome.

Fig. 1

Flowchart of patients included from the analysis

Fig. 2

Changes in lung function before and after treatment. Changes in FEV₁ (a), DLco (b) and FVC (c) before and after treatment. Bars and lines show the mean ± standard error of changes in lung function. Abbreviations: Pre_12M, 12 months before treatment; Post_12M, 12 months after treatment; Post_24M, 24 months after treatment; FEV₁, forced expiratory volume in 1 s; DLco, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity. ^*p < 0.05

Fig. 3

Categorical changes in lung function before and after treatment. Changes in disease progression (any decline in FEV₁) before and after treatment in all subjects a, in the low-dose group b and in the conventional-dose group c. Bars show the proportion of patients in each group. Abbreviations: Pre_12M, 12 months before treatment; Post_12M, 12 months after treatment; Post_24M, 24 months after treatment; FEV₁, forced expiratory volume in 1 s. ^*p < 0.05 (compared with 12 months before treatment)