disease is exclusive to women and is seen in 5 out of every million people. The
disease occurs sporadically.
in patients with LAM, the lung function declines and hypoxia develops within a
decade of symptoms appearing.
cells infiltrate the lung of LAM patients. They arise from an unknown source
and appear to be histologically benign. These cells show the presence of TSC
gene mutations. This results in activation of the mammalian target of rapamycin
(mTOR) signaling pathway. This pathway
regulates multiple cellular functions and controls growth, motility, and
The drug sirolimus (also called rapamycin)
has shown promise in the recent phase 1-2 trials
involving LAM patients. It blocks mTOR activation and restores homeostasis in cells with TSC gene mutation.
models of TSC gene mutation, sirolimus has shown to cause regression of
neoplastic growths in the kidney and liver.
However, the relative risks and benefits of the medication in patients
with LAM are not yet unclear.
Aim & Method of Study:-
An international, multicenter, randomized,
placebo-controlled study was conducted to assess if treatment with sirolimus
for a year would improve lung function in patients with LAM. The trial
details and protocol were as follows:-
• 12-month study randomized, double-blind
comparison of sirolimus with placebo
• This was followed by a 12-month observation period
• The study involved 89 patients with LAM who had
moderate lung impairment
eligible for the study were women aged 18 years or older who were diagnosed
with current or planned pregnancy, those with large chylous fluid collections,
or those who had a prior lung transplantation were excluded
patients provided a written informed
When compared to the placebo
group, the sirolimus group had improvement from baseline to 12 months in the
• Forced vital capacity,
• Functional residual capacity,
• Serum vascular endothelial
growth factor D (VEGF-D)
• Quality of life
• Some functional performance measures.
Once sirolimus was discontinued, there was a decline
in lung function in the sirolimus group and it equaled that in the placebo
more common in the sirolimus group in comparison to the placebo group. They include
mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash, and swelling
in the lower extremities. Rare cases of
cardiac events were observed in the sirolimus group.
Nevertheless, it was concluded that in LAM patients,
sirolimus stabilized lung function, reduced symptoms and improved quality of
The study therefore suggested that therapy
with sirolimus may be useful in selected LAM patients.
1.Francis X. McCormack, M.D., Yoshikazu Inoue, M.D., Ph.D et al; "Efficacy
and Safety of Sirolimus in Lymphangioleiomyomatosis"; N Engl J Med 2011; 364:1595-1606 April