Sirolimus (rapamycin), an mTORC1 inhibitor, is FDA-approved (May 2015) and EMA-approved (...
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| ID | BMA-TSC1-LAM |
|---|---|
| Tipo | Relevância terapêutica |
| Estado | reviewed 2026-05-04 | pending_clinical_signoff | actionability review required |
| Doenças | DIS-LAM |
| Fontes | SRC-MILES-MCCORMACK-2011 |
Fatos de ação
| Biomarcador | BIO-TSC1 |
|---|---|
| Variante | TSC1 ou TSC2 perda de função (contexto LAM — somático em LAM esporádico, linha germinativa em Lam associado TSC); a hiperativação mTORC1 é o alvo terapêutico independentemente da especificidade TSC 1 vs TSC2. |
| Doença | DIS-LAM |
| Nível ESCAT | IA |
| Combinações recomendadas | 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 |
| Resumo das provas | 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). |
Notas
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.
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