Precision Medicine Approach Resolves Severe Lung Disorder

A precision medicine approach that targeted a genetic mutation helped clinicians resolve a severe lymphatic disorder in a patient, according to a study published in EMBO Molecular Medicine.

The patient, a young woman named Brenna, had kaposiform lymphangiomatosis (KLA), a complex and rare disorder that causes lymphatic vessels around the heart and lungs to leak fluid, resulting in breathing difficulties, infection, and possibly death.

Brenna first developed symptoms related to KLA when she was six and was diagnosed with the disorder by age 10. For almost a decade, providers treated her with a range of therapies, including an immunosuppressant, a steroid, and a chemotherapy drug. When her symptoms persisted, the team set out to explore other therapies.

Many patients with KLA have a mutation in the NRAS gene, and the group had previously used a mitogen-activated protein kinase (MEK) inhibitor called trametinib in a different patient with a severe lymphatic disorder and NRAS mutation.

The drug was able to resolve his symptoms and completely remodel his lymphatic system. While that patient didn’t have KLA, researchers felt that the success of trametinib in treating his symptoms, combined with Brenna’s deteriorating condition, warranted expanded access to treat Brenna with the drug.

As Brenna began taking the drug, researchers sent samples of her lymph fluid for genetic sequencing. The team learned that she did not have a NRAS mutation, but instead had a mutation in the CBL gene, which operates along the Ras pathway and is implicated in other lymphatic disorders.

Mutations along the Ras pathway result in an overproduction of MEK, which results in the uncontrolled proliferation of lymphatic vessels. A MEK inhibitor like trametinib brings the production of MEK under control.

Within four weeks of starting a low dose of trametinib, Brenna’s symptoms improved, with her shortness of breath, coughing, and difficulty breathing while lying flat disappearing. During the second cycle of therapy, she was able to exercise again and began training for a 5K race.

These results show that trametinib may be used to effectively curb symptoms of lymphatic disorder, highlighting the potential for precision medicine therapies to improve chronic disease management.

"The relatively low dose required for dramatic improvement in this case highlights that a small amount of trametinib may be sufficient to treat lymphatic disorders, which will likely limit the side effect profile compared to the higher doses used for oncologic cases," said senior author Yoav Dori, MD, PhD, Director of the Jill and Mark Fishman Center for Lymphatic Disorders at CHOP.

"We are now preparing ongoing prospective studies to evaluate Ras pathway inhibition in clinical trials of large cohorts of patients."

In follow-up tests, Brenna’s restrictive lung disease has shown significant improvement, and the fluid in her lungs has disappeared. Her lymph vessels have remodeled themselves and are performing normally. Now, at 20 years old, she continues to take a daily dose of trametinib to keep her symptoms at bay.

"Genomic evaluation of vascular anomalies such as KLA have only just begun in recent years," said Denise Adams, MD, Director of the Comprehensive Vascular Anomalies Program (CVAP), a CHOP Frontier Program. "This case study demonstrates the power of collaborative, cutting-edge research that reaches across disciplines, from genetics to oncology to cardiology, to bring breakthrough treatments to patients."

This case study has significant implications for disease treatment and management in the future, researchers stated.

"The resolution of lung disease with lymphatic remodeling is remarkable and potentially should change how we evaluate and treat lung disease in this patient population," said first author Jessica B. Foster, MD, an attending physician in CHOP's Division of Oncology. "These results offer hope to other patients with lymphatic-induced lung disease and warrant further investigation."

Going forward, more research will be necessary to determine the impact of trametinib on other individuals.

“The relatively low dose required for dramatic improvement in this case highlights that a small amount may be sufficient to treat lymphatic disorders, which will likely limit the side effect profile compared with the higher doses used for oncologic cases. Ongoing prospective studies are now in preparation to evaluate Ras pathway inhibition in clinical trials of large cohorts of patients,” researchers concluded.

Researchers and providers are increasingly trying precision medicine treatments to help improve outcomes among patients with a range of conditions. Recently, a study published in Nature Communications showed that patients with advanced cancer who received precision medicine treatments were more likely to survive or have longer periods without their disease progressing than those who received standard therapies.

The team deployed a multidisciplinary tumor board (MTB) to advise treating physicians on the course of care.

“Overall, our MTB experience suggests that greater degrees of matching of tumors to drugs, including with customized N-of-one recommended combinations, was independently associated with better outcomes,” researchers stated.