From the Guidelines
The treatment approach for patients with Tuberous Sclerosis Complex (TSC) who develop Lymphangioleiomyomatosis (LAM) primarily involves mTOR inhibitors, specifically sirolimus (rapamycin) or everolimus, with sirolimus being recommended for patients with abnormal or declining lung function, as stated in the official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines 1.
Key Considerations
- The recommended starting dose for sirolimus is typically 1-2 mg daily, adjusted to maintain trough levels of 5-15 ng/mL, while everolimus is usually started at 2.5-5 mg daily, as supported by recent clinical practice recommendations 1.
- These medications are generally continued indefinitely as LAM often progresses when treatment is discontinued.
- Bronchodilators like albuterol may be used for airflow obstruction, and oxygen therapy is recommended when hypoxemia develops.
- Pulmonary rehabilitation should be considered for patients with exercise limitations.
- For women with TSC-LAM, hormonal therapy (avoiding estrogen) and careful pregnancy planning are important as estrogen can exacerbate LAM progression.
- Regular pulmonary function tests (every 3-6 months initially, then annually) and chest imaging are essential for monitoring disease progression.
Rationale
mTOR inhibitors are effective because they target the underlying pathophysiology of TSC-LAM, which involves dysregulation of the mTOR pathway due to mutations in the TSC1 or TSC2 genes, leading to abnormal smooth muscle-like cell proliferation in the lungs, as discussed in the European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis 1.
Advanced Disease
For patients with advanced disease, lung transplantation may be considered, though LAM can recur in the transplanted lung.
Recent Guidelines
Recent clinical practice recommendations suggest that sirolimus is a reasonable alternative to everolimus for mTORC1 inhibition in TSC, and that therapy can be started at 10 mg/day in adults or 4.5 mg/m2/day in children, with adjustments based on side effects and safety 1.
From the Research
Treatment Approach for Tuberous Sclerosis Complex (TSC) with Lymphangiomyomatosis (LAM)
The treatment approach for patients with Tuberous Sclerosis Complex (TSC) who develop Lymphangiomyomatosis (LAM) involves the use of mTOR inhibitors, such as sirolimus.
- The efficacy of sirolimus in reducing angiomyolipoma volume and improving lung function in patients with TSC or LAM has been demonstrated in several studies 2, 3, 4.
- Sirolimus has been shown to reduce the size of kidney angiomyolipomas by 30% or more in some patients, and to improve lung function in patients with LAM 2, 3.
- The use of mTOR inhibitors, such as sirolimus, is considered a promising therapeutic approach for the treatment of TSC-associated angiomyolipomas and LAM 5, 6.
Key Findings
- A 24-month, nonrandomized, open-label trial found that sirolimus reduced angiomyolipoma volume and improved lung function in patients with TSC or LAM 2.
- A phase 2 trial found that sirolimus induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas in patients with TSC 3.
- A multicenter phase 2 nonrandomized open label trial found that sirolimus reduced the size of renal angiomyolipomas in patients with TSC or sporadic LAM 4.
Treatment Considerations
- mTOR inhibitors, such as sirolimus, are considered the treatment of choice for LAM with moderately impaired lung function or chylous effusion 5.
- The use of sirolimus may be associated with adverse events, such as stomatitis, hypertriglyceridemia, and bone marrow suppression 2, 3, 4.
- Further studies are needed to determine the benefits and risks of longer duration treatment with sirolimus in adults and children with TSC 3.