Lyphangioleiomyomatosis (LAM) is a sporadic and rare but devastating lung disease. Cells with many of the characteristics of smooth muscle but of unknown origin infiltrate lung tissue leading to the formation of multiple cysts. Most patients eventually develop significant lung impairment, recurrent pneumothoraces, hypoxemia and die from these changes. LAM affects about five people per million in the U.S., largely young women. For a long time, it carried a bleak diagnosis with scarce treatment options.
The underlying pathology of LAM is considered to involve inappropriate activation of the mammalian target of rapamycin (mTOR), a cellular growth regulator. When overactive, mTOR signaling promotes excessive growth, including lymphangiogenesis.
Previous studies had suggested that sirolimus, a drug that inhibits mTOR, might hold therapeutic benefit for patients with LAM, but until recently, no controlled trials had been conducted to test this claim.
Last month in NEJM, McCormack et al. reported the results of the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial, a randomized, double-blind trial that evaluated sirolimus as a potential treatment for patients with LAM. Eighty-nine patients with LAM and moderate lung impairment enrolled; half were assigned to receive sirolimus treatment and the other half to receive placebo.
The trial was conducted in two stages. For the first year, patients received therapy according to their assigned treatment arm; for the next year, both patient groups received no treatment and were simply observed. The primary endpoint was the between-group difference in change of forced expiratory volume in 1 second (FEV1), a commonly used indicator of lung function, over the year of observation. This was called the FEV1 slope; large negative slopes indicate rapid loss of lung function.
The patients in the sirolimus treatment arm, as compared with those in placebo, had an improvement in the FEV1 slope. The study also demonstrated that treatment with sirolimus reduced levels of vascular endothelial growth factor D (VEGF-D) and improved quality of life in LAM patients. However, once treatment was stopped, the benefits of sirolimus also disappeared — patients in the sirolimus group experienced a decline in lung function at close to the same rate as patients in the placebo group.
Treatment with sirolimus was associated with an overall greater number of adverse events as compared with placebo; these included blood/bone marrow, gastrointestinal, and dermatologic problems. However, sirolimus use was not associated with a higher frequency of serious adverse events, such as pericarditis or arrhythmias, as compared with placebo.
Overall, these findings suggest that sirolimus may be a valuable treatment option for patients with LAM. In an accompanying editorial, NEJM deputy editor Julie Ingelfinger, M.D., and editor-in-chief Jeffrey Drazen, M.D., write, “even though these data offer women with LAM the prospect of only a longterm treatment rather than a cure, this is a big step forward. Twenty years ago, it would have been impossible to make this much progress in such a rare disease. This research study shows that when patients and researchers work together toward a common goal, advances can be made.”
When approaching patients with a rare disease like LAM, how do you get help? Do you turn to internet resources to see if there are patient advocacy groups that may offer participation in diagnostic or therapeutic trials? Do you encourage your patients to do this