Sirolimus for Lymphangioleiomyomatosis
This is Andy Shorr from the Washington Hospital Center with a pulmonary and critical care literature update.

I would like to point out an article that was in the April 28 issue of The New England Journal of Medicine by McCormack and colleagues. These investigators performed a randomized controlled trial looking at issues related to the treatment of lymphangioleiomyomatosis (LAM). LAM is an exceedingly rare disease but one that is potentially catastrophic in terms of its implications. LAM is a multisystem disease, affecting not only the lungs but other organs as well. LAM is usually, if not always, seen in women because otherwise the patient might have tuberous sclerosis.

We have had very few therapies and in the past women have been offered all sorts of options, such as removing their ovaries to suppress hormone production, to control this disease. LAM remains a very important orphan disease that has been supported by many patient advocacy efforts, as evidenced by the relationship between the LAM Foundation and both the American Thoracic Society and the American College of Chest Physicians.

In this study, McCormack and colleagues looked at the question of whether sirolimus as an immunosuppressive agent affected outcomes in this disease. They performed a well-done, double-blind, randomized, controlled trial in which approximately 90 patients were randomly assigned to either sirolimus (with the drug level titrated to 5-15 ng/mL) or placebo. A nonblinded physician adjusted the dose and also performed "sham" or "dummy" adjustments in the patients assigned to placebo to ensure that everybody remained blinded. That is important in a dose titration study.

The primary endpoint was change in forced expiratory volume in 1 second (FEV1) and a there were a number of secondary end points. The population was exactly what you would expect. These patients had moderately impaired lung function and evidence of LAM. They had very high elevations of their vascular endothelial growth factor (VEGF)-D levels, which is an important marker of this disease and may, in fact, be pathogenic as well.

Over the course of a year, the investigators saw that the patients assigned to sirolimus had improvements not only in FEV1 but also in forced vital capacity. They also had substantial improvements in quality of life compared with patients who were given placebo.

Let me be clear here. Lung function in the patients who were randomly assigned to sirolimus actually improved. The rate of change was better than the rate of absolute value change in the patients given placebo, whose lung function was declining in an accelerated fashion.

After a year, the investigators stopped the study but continued blinded observation for another year, when patients were no longer taking the drug. They looked again at the rate of change and found that once patients stopped taking sirolimus, the drug's beneficial effect deteriorated and decayed very quickly. Patients who had formerly taken sirolimus and who had improvement in lung function regressed over the course of a year, and the trajectory of their lung function declined.

This study clearly demonstrates that sirolimus offers an important therapeutic intervention in patients with LAM. In essence, the change in FEV1 between the treated patients and the placebo patients was approximately 150 cc. Remember, we consider a 100-cc change in FEV1 as the minimally clinically important difference for patients with chronic obstructive pulmonary disease. That likely explains why quality of life differed between the 2 groups -- better lung function, better quality of life. Of interest, there were no differences in diffusing capacity or in 6-minute walk distance, but the study was underpowered to look at those end points.

Rarely, especially for diseases that are infrequent, do we have randomized controlled trial data to guide us. More importantly, we often lack data that show a correlation between physiologic lung function changes and the quality-of-life measures that really are important to our patients. This study is unique both in tying those things together and studying a very challenging disease but also in having the foresight to look more than a year later at what happens when patients stop taking the drug. This really proves that the drug had an effect because when you take it away the effect that you have ascribed to the drug has dissipated. These investigators are to be commended for their trial.

Another unique aspect of this trial was that it reflected a collaboration between physician investigators, clinicians, and patient advocacy groups. It represents a model for a number of other diseases for us to look at in the future. Sirolimus has toxicities, and more adverse advents were seen in the patients who took sirolimus compared with those who took placebo, However, the rate of serious adverse events was not different and no increased rate of drug discontinuation as a result of adverse events was observed.

In the end, these are excellent data suggesting that sirolimus is important in these patients. In addition, McCormack and colleagues saw that as they treated with sirolimus, the VEGF levels came down, suggesting that VEGF can be an important marker of disease activity or even serve as a screening test for this disease in our evaluation of patients with cystic lung findings on CT scan.

I urge you to look at this article from the April 28 issue of The New England Journal of Medicine. This is Andy Shorr from Washington, DC.