Original articleThe efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis
Introduction
Lymphangioleiomyomatosis (LAM), a rare disease seen primarily in women of childbearing age, is characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells), which lead to cystic destruction of the lungs, chylous effusions, lymphangioleiomyomas, and, frequently, renal angiomyolipoma (AML) [1], [2]. This condition can occur as a sporadic disease (sporadic LAM) or as a pulmonary manifestation of tuberous sclerosis complex (TSC) (TSC-associated LAM) [3], [4], [5]. The apparent cause of TSC-associated LAM is mutation of either of the tumor suppressor genes TSC1 and TSC2, whereas sporadic LAM results mainly from mutation of TSC2 [6], [7], [8]. Loss of TSC gene function allows constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway, which regulates multiple cellular functions such as growth, motility, and survival [9].
The mTOR inhibitors such as sirolimus and everolimus block mTOR-mediated activation of downstream kinases and restore homeostasis in cells with defective TSC gene function [9]. Administration of mTOR inhibitors has previously been shown to decrease the size of AML and stabilize lung function in patients with LAM [10], [11]. The CAST (Cincinnati Angiomyolipoma Sirolimus Trial) was a phase 1–2 trial comprising 20 patients with TSC or sporadic LAM, and sirolimus reduced the size of renal AML in both groups [10]. In that study, the optimal dose for the reduction of AML was determined by first administering sirolimus at 0.25 mg per square meter of body-surface area to achieve a blood trough level between 1 and 5 ng/mL (1–5 ng/mL). If this did not decrease the size of the target AML by 10% of the baseline value within 2 months, the dose was increased to achieve a trough level of 5–10 ng/mL. Finally, if the lesion did not decrease in size by 10% of the baseline value within 4 months, the dose was increased to achieve a trough level of 10–15 ng/mL, and that dose was continued throughout the next 12 months. Under this regimen, 1 of the 20 patients remained at the initial target trough level of 1–5 ng/mL, whereas the other 19 patients were dosed to reach the highest target level (10–15 ng/mL).
The MILES (Multicenter International LAM Efficacy of Sirolimus) Trial was a double-blind, placebo-controlled trial in which sirolimus was shown to stabilize lung function and improve the quality of life in patients with LAM [11]. In that trial, sirolimus was administered to maintain blood trough level of 5–15 ng/mL, which was chosen on the basis of results of the CAST. However, it remains unclear whether this is the optimal level for the treatment of LAM, especially as other recent case reports have shown that a lower dose was also effective [12], [13]. Therefore, to determine the efficacy and safety of sirolimus at a concentration lower than the currently recommended trough level, we conducted an observational study of Japanese patients with LAM who took sirolimus at doses that maintained blood trough levels lower than the currently recommended target of 5–15 ng/mL.
Section snippets
Study population
Records from 21 patients with LAM who were treated with sirolimus in the Department of Respiratory Medicine at Juntendo University Hospital between November 2009 and January 2012 were reviewed for this study. We excluded 6 patients for the following reasons: 2 patients discontinued sirolimus treatment within 2 months due to adverse events (drug-induced lung injury and skin rash/chest discomfort, respectively), 1 patient lacked serial data, 2 patients received sirolimus for too short a period to
Trough sirolimus levels in the blood
Of the 15 patients treated with sirolimus who are reviewed here, all had trough blood levels lower than 5 ng/mL (mean, 2.16 ng/mL; range, 0.8–4.3 ng/mL). Accordingly, we arbitrarily designated the treatment regime “low-dose sirolimus treatment” because the trough levels of all patients were lower than those in previous studies [10], [11], [16], [17].
Effect of sirolimus on pulmonary function
The clinical characteristics of the 8 patients without chylous effusion are shown in Table 2. All of these patients had sporadic LAM, and their ages
Discussion
This retrospective study documents the effectiveness of low-dose sirolimus for stabilizing pulmonary function and decreasing chylous effusion in patients with LAM. Our results resemble those of previous studies in which the blood trough level of sirolimus was maintained at 5–15 ng/mL [11], [16], [17]. Therefore, our data indicate that sirolimus was effective in Japanese patients even at a trough level less than 5 ng/mL. A particularly noteworthy patient was JUL97, a woman with atypical symptoms
Source of support
This study was supported by a grant to the Respiratory Research Group from the Ministry of Health, Labour, and Welfare, Japan; in part by the High Technology Research Center Grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and in part by the Institute for Environmental and Gender-Specific Medicine, Juntendo University, Graduate School of Medicine.
Conflict of interest
The authors have reported to Respiratory Investigation that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in the article.
Acknowledgment
We thank Phyllis Minick for excellent assistance with English usage.
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Deceased. Dr. Masashi Mikami, partly contributed to the acquisition of data.