Sirolimus (rapamycin), an mTORC1 inhibitor, is FDA-approved (May 2015) and EMA-approved (...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-TSC1-LAM |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-05-04 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-LAM |
| Sources | SRC-MILES-MCCORMACK-2011 |
Actionability Facts
| Biomarker | BIO-TSC1 |
|---|---|
| Variant | TSC1 or TSC2 loss-of-function (LAM context — somatic in sporadic LAM, germline in TSC-associated LAM); mTORC1 hyperactivation is the therapeutic target regardless of TSC1 vs TSC2 specificity |
| Disease | DIS-LAM |
| ESCAT tier | IA |
| Recommended combinations | sirolimus (target trough 5–15 ng/mL; start 2 mg/day PO, adjust to trough; continuous indefinitely for progressive LAM), everolimus 10 mg PO QD (TSC-associated LAM and renal AML; EXIST-2 dosing) |
| Contraindicated monotherapy | sirolimus in pregnancy — embryo-fetal toxicity; mandatory contraception, hormonal contraceptives (estrogen-containing) — LAM is estrogen-sensitive; progesterone-only or non-hormonal methods preferred |
| Evidence summary | Sirolimus (rapamycin), an mTORC1 inhibitor, is FDA-approved (May 2015) and EMA-approved (2017) for treatment of LAM in adults. MILES phase III RCT (McCormack et al., NEJM 2011): N=89 (46 sirolimus, 43 placebo); 12-month treatment + 12-month observation. Primary endpoint: FEV1 change from baseline to 12 months (mL/month rate). FEV1 slope: +1 mL/month (sirolimus) vs -12 mL/month (placebo); difference 11 mL/month (p<0.001). Secondary: FVC improvement, VEGF-D reduction, 6-min walk improvement, QoL. After 12-month observation: benefits partially lost (FEV1 decline resumes), suggesting need for continuous therapy. mTOR inhibition does not eliminate LAM cells but controls their mTORC1-driven proliferation. Everolimus is used for TSC-associated LAM and for renal angiomyolipoma (EXIST-2). VEGF-D ≥800 pg/mL is a diagnostic biomarker (non-invasive diagnosis of LAM possible in right clinical context without biopsy). |
Notes
ESCAT IA (FDA-approved, phase III RCT). Sirolimus does not cure LAM — TSC1/TSC2-deficient LAM cells persist but their mTORC1-driven proliferation is suppressed. Therapy is indefinite. Monitoring: pulmonary function tests (PFTs) q3–6 months; HRCT annually or if symptoms change; sirolimus trough levels (target 5–15 ng/mL); VEGF-D (diagnostic and monitoring). Drug interactions: sirolimus is a CYP3A4 substrate and inhibitor — avoid strong CYP3A4 inhibitors (azoles increase sirolimus levels) and inducers (rifampin decreases levels). TSC-associated LAM vs sporadic LAM: clinical management identical; TSC patients also need surveillance for SEGA, renal AML (both everolimus-treatable), and other TSC manifestations. Lung transplantation: reserved for advanced LAM (FEV1 <40% predicted, significant hypoxemia); sirolimus is typically held peri-transplant (impairs healing) and restarted post-transplant in some centers.
Used By
No reverse references found in the YAML corpus.