Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare multisystem neoplastic disease that is characterized by cystic lung destruction, angiomyolipoma and lymphangioleiomyomas [1, 2]. LAM may occur sporadically, or in adults with tuberous sclerosis complex [1]. Cystic remodeling in the lungs compromises lung function, resulting in progressive dyspnea, and finally respiratory failure [3].

Sirolimus (rapamycin) has been confirmed to be effective for the treatment of LAM [4, 5]. In our previous report, sirolimus was shown to improve lung function, arterial oxygen levels, 6 min walking distance (6MWD), St George Respiratory questionnaire (SGRQ) scores and vascular endothelial growth factor (VEGF-D) levels [6]. However, the long-term effects of sirolimus are unclear. Several studies included data on sirolimus treatment over a 2-years period [7‐12]. Taveria-DaSilva et al. [8] reported a study in which 44 patients were treated with sirolimus alone, the changes of predicted values of FEV₁ and DLCO were − 1.7% ± 0.1% and − 2.2% ± 0.1% before treatment and + 1.7 ± 0.3% and + 0.7% ± 0.3% after treatment (P <  0.001) during a mean of 2.8 years follow up time. In the recent study, Taveira-DaSilva et al. [9] evaluated the change of pulmonary function of 25 patients with sirolimus treatment, over a period of 4.5 ± 1.6 years, in which annual changes in forced expiratory volume in 1 s (FEV₁) and diffusion capacity for carbon monoxide (DLCO) were reduced from − 7.4% ± 1.4% to − 0.3% ± 0.5% (P <  0.001) and − 6.4% ± 0.9% to − 0.4% ± 0.5% (P <  0.001), respectively. Johnson et al. [10, 11] prospectively observed LAM patients treated with sirolimus over 2 years, the mean change in FEV₁ ranged from − 7 ± 82 ml/year (n = 23) to 11 ± 75 ml/year(n = 47). The above studies demonstrated that sirolimus effectively improves the lung function in LAM patients. However, it is still unknown whether sirolimus continuously improves or stabilizes lung function over a longer observation period.

Considering sirolimus is used in LAM patients for a long period of time, whether its efficacy can be maintained is a critical question. Safety is another issue for those patients who take sirolimus for many years. In this study, we analyzed the efficacy and safety of sirolimus for up to 4 years.

Whether the efficacy of sirolimus can be maintained during long-term treatment is a critical question. We partially answered this question in the present study. We found improvements of sirolimus in the following parameters in patients after beginning sirolimus treatment: the FEV₁ in the first year; the FVC in the first and second year; arterial oxygen levels, exercise capacity and quality of life in the first, second and third year; and the VEGF-D levels in all 4 years. An encouraging finding was that most measurements improved or stabilized during 4-year observations after sirolimus treatment.

Current clinical trials usually observed 12–24 months of sirolimus treatment. Several studies included observations over 2 years. In studies with 2–4 years observation, the increase in the FEV₁ varied from 11 ml/year to 50 ml/year after starting sirolimus treatment [6, 7, 10‐12]. In a 4-year prospective study, the mean change in the FEV₁ in patients not receiving sirolimus was -70 ml /year (n = 66), while the mean change in patients receiving sirolimus was 7 ml/year (n = 23) [10]. Taveira-DaSilva et al. [9] observed 25 patients for 4.5 years, and the FEV₁ and DLCO changed slightly. The change of FEV₁ was − 10 ml/year (P = 0.53) and the FVC increased by 54 ml/year (P = 0.016) in our study. In the paired comparison analysis, we found that the FEV₁ benefited most from sirolimus in the first year, and the FVC benefited in the first 2 years. No significant reduction in pulmonary function was observed over the 4 years. The efficacy of sirolimus can be maintained for at least 4 years.

Higher VEGF-D levels were observed more frequently in patients with lymphatic disease who presented with chylous pleural effusion or ascites than in patients without lymphatic involvement [17]. Several studies reported that compared with patients without lymphatic disease, patients with lymphatic involvement may experience a great improvement in pulmonary function after starting sirolimus therapy [7, 9]. Taveira-DaSilva et al. [9] observed that the effects of sirolimus on VEGF-D levels and DLCO were especially marked in patients with LAM with lymphatic involvement than those without lymphatic involvement. For patients with or without limited small amount of chylothorax, improvement of pulmonary function was similar.

The safety profile is satisfactory. Patients tolerated sirolimus treatment very well. The rate of adverse effects decreased during the follow-up. We also analyzed the group of patients who were followed up for 3 and 4 years, the rate of adverse effects were decreased over time (data not shown).

Anyway, we still need to be cautious in observing long-term adverse effects from the treatment. LAM patients use sirolimus for many years, and it is important to monitor their progress and safety data regularly, at least once a year. Novel therapies for LAM are urgently needed for use when sirolimus cannot be used because of insensitivity or resistance of sirolimus.

The limitations of this study include its retrospective nature and the limited sample size during observation, as only 32 patients had data for all 4 years. Beginning in 2016, a national LAM registry in China was planned that will recruit 800 LAM patients and conduct yearly follow-up. We hope that some unanswered questions will be clarified in future studies.

In conclusion, sirolimus therapy is effective at improving or stabilizing pulmonary function, oxygen levels, exercise capacity, and quality of life in patients with LAM for up to 4 years. VEGF-D maintained at lower level for 4 years after the initiation of treatment. Adverse events related to sirolimus was mild during the follow-up period.