The first-time patient at the Center for LAM Research and Clinical Care at Brigham and Women’s Hospital was typical: A female in her 30s, she had experienced dyspnea on exertion, unusual chest discomfort and fatigue for years. The otherwise healthy former athlete had seen multiple physicians, who ruled out cardiac issues and prescribed asthma meds, but symptoms persisted. When a CT scan was ordered for a suspected pulmonary embolus, none was found. But the scan revealed the real problem: Lung destruction that is characteristic of lymphangioleiomyomatosis (LAM).
Nearly 200 miles from home, at The Lung Center at Brigham and Women’s Hospital, the patient finally had a confirmed diagnosis and rapid initiation of proven treatment to stabilize the rare, progressive disease.
Approximately 2,000 women in the United States have been diagnosed with LAM, “but we think many more are living with undiagnosed LAM,” said Elizabeth (Lisa) Henske, MD, an oncologist and LAM pioneer who leads the LAM center with clinical director Souheil Y. El-Chemaly, MD, a pulmonologist and LAM investigator. “It is so important now to make the diagnosis of LAM because we have a treatment – sirolimus – that can delay lung function decline. But we need to find the disease early, before there is extensive lung destruction.”
LAM occurs almost exclusively in females and can affect women with tuberous sclerosis complex (TSC) or occur in a sporadic form. LAM is caused by the diffuse proliferation of LAM cells, which cause cystic lung destruction. Because characteristic symptoms are non-specific (shortness of breath, fatigue, unusual chest pain), a LAM diagnosis is often overlooked. Symptoms typically begin in the 20s or 30s, often after pregnancy. Even women who experience a pneumothorax, a hallmark of LAM, may not be diagnosed with LAM unless a chest CT scan is ordered, revealing the tell-tale cysts.
CT, Biomarker Test and Proven Treatment Can Halt or Delay Progression
In recent years, the rapid pace of basic and translational research in LAM has clarified diagnosis and identified a treatment (sirolimus/rapamycin) that halts or delays disease progression. Research by Dr. Henske and others in the 20-person LAM research group at Brigham and Women’s has provided significant momentum. Recent progress in the LAM field includes:
- Vascular endothelial growth factorbiomarker VEGF-D is now a diagnostic biomarker for LAM
- Biopsy is not necessary in women with diffuse thin-walled cysts and a VEGF-D level >800 pg/ml
- Treatment with sirolimus (also known as rapamycin) can halt lung deterioration
“We’ve made huge progress in LAM. Now, in almost every case, we can keep a woman from losing additional lung function,” said Dr. Henske. “For someone whose FEV1 is 70% of predicted when diagnosed with LAM, we can keep her at 70% with sirolimus/rapamycin, with side effects that are usually tolerable.” The medication must be continued indefinitely to keep progression at bay.
Every time a pulmonologist or thoracic surgeon orders a CT scan and a confirmatory VEGF-D test when faced with this vague constellation of symptoms or lung collapse, Dr. Henske said, the results could be life-changing.
Collaborative Care at Brigham and Women’s Advanced LAM Center
Brigham and Women’s Hospital’s Center for LAM Research and Clinical Care is among a handful of treatment centers in the US and offers one of the largest research portfolios and patient care programs. The clinic now follows approximately 155 patients from the northeastern US and beyond.
After a diagnosis of LAM at the Center, a patient and physician discuss whether rapamycin treatment should begin immediately or be delayed, sometimes weighing potential side effects against the women’s family planning, Dr. El-Chemaly said. Patients generally see a physician every four to six months, alternating between a pulmonologist in their home community and one of the center’s seven LAM specialists.
Dr. Henske’s training and work as a clinical oncologist at the Dana-Farber/Brigham and Women’s Cancer Center creates a unique interdisciplinary approach. “LAM seems to be in the gray zone between an interstitial lung disease and a low-grade malignancy,” she said. While nearly all clinical care for LAM is provided by pulmonologists, about half of ongoing research is done by oncologists.
Rapid Research Progress from Bench to Bedside
Dr. Henske’s research in the late 1990s set the foundation for rapid progress from basic science to effective treatment for LAM, starting with her discovery of mutations in the TSC2 gene that cause the sporadic form of LAM. Knowledge that rapamycin was effective in other settings where TSC2 was mutated led quickly toward sirolimus as a potential therapy.
In 2011, a study published in the New England Journal of Medicine showed that sirolimus stabilized lung function, reduced VEGF-D levels and brought an associated improvement in quality of life. Hilary J. Goldberg, MD, now medical director of the Brigham’s Lung and Transplant program, was among the investigators.
Research continues to be fully integrated with clinical care at the Center for LAM Research and Clinical Care. Patients have access to key trials, including the 2017 SAIL trial of combined sirolimus and hydroxychloroquine, led by Dr. El-Chemaly and Dr. Henske. Other recent research from the LAM Center includes:
- Evidence that serum endostatin could be a predictive biomarker in the decline of diffusion capacity of the lungs for carbon monoxide (DLCO)
- Analysis from the SAIL trial that identified additional potential markers that could be linked to disease pathogenesis, lung injury and therapeutic response
- Increased understanding of dysregulation of VEGF-D in LAM that could lead to new therapies
- New evidence that immunotherapy could be effective in LAM
With such an active clinical and research program, the Brigham’s LAM team is optimistic that the rapid pace of discovery and translation will continue.
“This remarkable progress in a rare disease wasn’t just by chance, but through a series of basic and translational research initiatives,” said Dr. Henske. “We look forward to the next breakthrough.”
To refer a patient to the Center for LAM Research and Clinical Care, call 1-844-BWH-LUNG (1-844-294-5864).