Summary of Lymphangioleiomyomatosis (LAM)
ICD-9 code for LAM is 516.4.
Lymphangioleiomyomatosis, better known as LAM, is a rare, cystic lung disease associated with mutations in tuberous sclerosis genes, renal angiomyolipomas, lymphatic spread and remarkable female gender restriction. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections. Lung function declines at approximately 2-3 fold times rate of normal subjects, based on an annual drop in forced expiratory volume in one second (FEV1) of 75-120 cc in various reported series.
The diagnosis of pulmonary LAM can be made on high resolution CT scan with a reasonable degree (>80%) of certainty by expert radiologists, but generally requires a lung biopsy in cases where tuberous sclerosis complex, angiomyolipomas or chylous effusions are absent. Measurement of serum vascular endothelial growth Factor D has been considered to be supportive for the diagnosis if available.
Currently available treatment strategies for LAM are based on antagonism of estrogen action, and are empiric and unproven. A trial of bronchodilators is warranted in LAM patients with reversible airflow obstruction on pulmonary function testing. Pleurodesis should be performed with the initial pneumothorax in each hemithorax because the rate of ipsilateral recurrence is over 70%. Angiomyolipomas that exceed 4 cm in size are more likely to bleed and should be evaluated for embolization. Air travel is safe in most patients with LAM. Lung transplantation is an important option for women with LAM, and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis in most patients. From the recent publications, sirolimus may be considered as a trial on an individual basis in progressive patients with possible benefit, after careful evaluation of risk/benefit ratio in an experienced centre.
There have been great strides in the basic science of LAM in the past fifteen years, due in large part to a confluence of scientific discoveries from the tuberous sclerosis and signaling biology fields, and remarkably effective, grass roots patient advocacy. Multicenter LAM clinical trials based on several well-defined molecular targets are currently underway or have just finished in the United States, Europe, Canada, and Japan. To read more about them click below:
MILES Trial (US, Canada, Japan)
TESSTAL Study (UK)
TSC Multicenter Clinical Trial (US)
TRAIL Trial Now Enrolling
What is the purpose of this study?
The purpose of the TRAIL (Trial of Aromatase Inhibition in LAM) Trial is to find out if a medication called letrozole slows the rate of decline in lung function in postmenopausal women with LAM when compared to a placebo. Letrozole is approved by the United States Food and Drug Administration to help prevent recurrence of breast cancer. The use of letrozole to treat LAM is experimental and has not been approved by the FDA.
Who may be eligible to participate?
- You may be eligible to participate if:
- You are 18 years old or older.
- You have been diagnosed with LAM.
- You are postmenopausal (naturally, surgically, or medically).
- Your lung function is abnormal (low forced expiratory volume in one second, low diffusing capacity or evidence of air trapping).
You should not participate if:
- You have a known allergy to letrozole.
- You have had treatment with other investigational medications within 30 days of screening.
- You have taken hormonal treatment (for example, progesterone) within 30 days of screening.
- You have untreated osteoporosis.
- You have had a lung transplant.
What is involved?
Women who enroll in the study will be involved for about one year. Participants will take either letrozole or a placebo every morning. Those who are determined eligible to participate will be “randomized” by chance (like flipping a coin) into two groups. One group will receive the study medication; the other, a placebo (an inactive substance that looks like the study medication. There is an equal chance (50-50) of being placed into either group. Neither the study staff nor you will know what group you are in. After the first visit, you will have visits every three months. Each visit will take about four hours, and may include: a physical exam, questionnaires, pulmonary function tests, bone density scan (Dexa scan), and blood draws. In addition, you will be asked to keep records of all medication taken during the study, including assigned study medication or placebo and any prescription or over-the-counter medications. A detailed list of tests and procedures is available if you want to know more about this study.
What are the benefits?
You may or may not benefit from participating in this study. You may benefit from the physical exams, pulmonary function tests, and other study procedures. Other potential benefits may include stabilization or improvement in lung function, and stabilization or decrease in the size of any kidney tumors (angiomyolipoma) or lymphangiomyomas (enlarged lymphatic vessels and nodes). The information gained from this study may benefit other patients with LAM in the future.
What are the risks?
There may be some risks and discomforts, including potentially serious risks, involved with participation in the study. A detailed list of possible side effects will be provided if you want to know more about this study.
Are there any costs to participate?
Tests and exams that are a normal part of your routine care for LAM are your or your insurance company’s responsibility. You should check with your insurance company to determine what costs associated with participation are covered. All research-related medication and tests will be provided at no cost to you.
How is the study funded?
The TRAIL Trial is being funded by grants provided by the Department of Defense and The LAM Foundation. Novartis provided the drug and placebo, but has no role in study design or conduct.
Is there pay for participation?
You will not receive any financial compensation for participation in this research study.
Where and when will the study be done?
The TRAIL Trial will be conducted in a subset of LAM Clinics. TRAIL sites will be chosen based on many factors, including the number of patients available for study and the resources available for trials.
Trial sites that are currently enrolling:
- Cleveland Clinic
Diane Faile, BS, RRT: 216.444.9975 or firstname.lastname@example.org
- Stanford University Medical Center
Susan Jacobs, RN, MS: 650.725.8082 or email@example.com
- Washington University School of Medicine / Barnes Jewish
St. Louis, MO
Tammy Koch, RN, BSN: 341.747.3063 or firstname.lastname@example.org
- Loyola University Medical Center
Catherine Kalnicky, RN, BSN: 708.216.2027 or email@example.com
Additional sites will be opening soon. Contact Tammy Roads at 513.558.2148 or via email at firstname.lastname@example.org for a list of current trial sites.
The Future - LAM Clinical Trials
LAM and TSC researchers have identified a wealth of potential molecular targets and experimental therapies that may be appropriate for testing in clinical trials. These include mTOR inhibitors (e.g., sirolimus, everolimus), Rheb inhibitors (e.g., farnesyltransferase inhibitors and statins), selective estrogen antagonists (e.g., fispemifene), tyrosine kinase inhibitors (e.g., imatinibmesylate), metalloproteinase inhibitors (e.g., doxycycline), angiogenesis inhibitors (e.g., bevacizumab), and lymphangiogenesis inhibitors (e.g., anti-VEGF-D antibody). Many of these drugs are FDA approved or in development for other indications. In the absence of a known effective treatment, participation in clinical trials should be encouraged. Widespread off label use of candidate therapies like those above will deprive patients of the opportunity to find an effective treatment, and condemn LAM to the same fate as dozens of other pulmonary diseases where the prospects for controlled trials have passed us by.
The LAM Foundation's Role
The LAM Foundation is committed to supporting the development of effective treatments for LAM. The Foundation has committed the majority of the $13 million raised to date to support 75 peer-reviewed research projects for the study of lymphangioleiomyomatosis (LAM), many of which have provided the scientific basis for current and future trials. Annual LAM scientific meetings organized and sponsored by The LAM Foundation have become the primary forum for presentation of landmark LAM research and scientific exchange. The National Heart, Lung, and Blood Institute has shown tremendous support for LAM by investing more than $20 million to support LAM conferences, a national registry of LAM patients and a LAM protocol that evaluates LAM patients. The stage is set. LAM is poised for great advances!