Matthew Holbreich was a senior in college when the swelling started. He originally thought he injured his left leg playing squash, but the intensity of the swelling scared him.
After seeing a few doctors in Boston, where he was living at the time, he eventually was referred to Stanford Medicine’s Stanley Rockson , MD. A trip across the country resulted in a new diagnosis: lymphedema, a condition in which excess lymph fluid accumulates in a patient’s arms or legs rather than draining through the lymphatic system into the bloodstream as it should.
It’s been 23 years since that diagnosis. Holbreich has given up contact sports, although he tries to live as normal a life as his chronically swollen leg allows. He’s had two infections that required hospitalization — lymphedema patients are prone to recurrent infections from skin microbes that infiltrate the swollen tissue. He also wears a compression stocking every day, and twice a year undergoes extensive physical treatments that involve lymphatic massage and tight, heavy wrapping of his leg.
“There’s currently no treatment for lymphedema other than wrapping,” Holbreich said. “It’s very antiquated.”
To date, there’s no approved medication for lymphedema. But Holbreich and Rockson are hopeful that could change soon. Holbreich was a participant in a recently completed clinical trial conducted at Stanford Medicine and led by Rockson, the Allan and Tina Neill Professor in Lymphatic Research and Medicine.
Holbreich, who himself works for a clinical trial software company, and 22 other study volunteers with lymphedema of the lower limbs took acebilustat, an experimental oral medication, once a day for a year. The result: The drug, which targets one key part of the inflammatory pathway that triggers lymphedema, effectively alleviated many of the disease’s most burdensome symptoms. Rockson and his colleagues authored a study describing these results that was published Sept. 30 in Scientific Reports . Rockson is the senior author; Catharine Bowman , a PhD candidate in epidemiology and population health, is the lead author.
“The prospect of having a medication for lymphedema would be life-changing,” Holbreich said. “I’ve been living with lymphedema for more than 20 years. It would be the most significant breakthrough for lymphedema treatment in my lifetime.”
An unappreciated condition
Lymphedema is a common but underappreciated condition, Rockson said. An estimated 10 million people in the U.S. have it, and likely hundreds of millions globally. As the disease progresses, the limbs change their underlying architecture in response to the additional fluid. The affected limb’s skin thickens, and extra fat and scar tissue build up underneath it. The condition can be painful, limit physical activity and dramatically change patients’ appearance.
Lymphedema can happen in response to lymph node damage, as commonly occurs with radiation or surgery for several types of cancer, notably breast cancer and gynecologic cancers. Other conditions such as obesity, heart failure, sleep apnea and venous hypertension also increase the risk of lymphedema. And some cases seem to have a genetic basis, cropping up early in life with no other risk factors besides a family history. It’s also more common in women, in part because so too are many of its risk factors, such as breast cancer.
For treatment, patients typically undergo time- and resource-intensive physical therapy, wear bulky compression garments, and use special compression machines on the affected limbs for an hour or more every day. For many, this regimen only slows the progression of the disease, Rockson said.
“Realistically speaking, the best we’re able to achieve with those interventions is about a 50% reduction in the severity of the disease, and often much less than that,” he said. “It’s very labor-intensive, there’s a tremendous impact on quality of life to undertake this self-management and it’s expensive.” Those costs are often the patients’ burden as insurance companies typically don’t fully cover the treatments.
The biology of lymphedema
Physicians have long believed that the later stages of lymphedema, where the limbs have accumulated extra skin, fat and scar tissue, are irreversible. In the mid-1990s, Rockson decided to delve into lymphedema biology to see if these changes could, in fact, be reversed.
He and his laboratory team developed a mouse model of lymphedema in which animals accumulate extra fluid and tissue in their tails; they found that inflammation underlies the disease. Specifically, a group of inflammatory molecules known as the 5-lipoxygenase, or 5-LO, pathway appeared to play a role. Rockson later led a pair of clinical trials showing that an anti-inflammatory drug, ketoprofen, that targets this pathway alleviates symptoms of lymphedema. Unfortunately, long-term use of drugs like ketoprofen was later found to raise the risk of heart disease. Holbriech was also a participant in the ketoprofen trial.
“We didn’t want to trade a non-life-threatening disease for a life-threatening one,” Rockson said.
It was back to the drawing board. Through further lab studies, the team identified a protein in the 5-LO pathway responsible for ketoprofen’s beneficial effects; the protein is called leukotriene B 4 , or LTB 4 . Patients with lymphedema have higher than normal levels of this protein in their blood. And when the scientists blocked LTB 4 activity in mice with tail lymphedema, their symptoms improved.
Targeted repair
The experimental drug tested in the recently completed clinical trial, acebilustat, halts LTB 4 production. It’s an even more targeted approach to lymphedema treatment than using ketoprofen, which also acts on other inflammatory systems in the body. Acebilustat seems to act only on the 5-LO pathway.
Although the clinical trial testing the drug was small and did not include a placebo group, the results show that acebilustat may be even more powerful against lymphedema’s effects than ketoprofen was. Patients lost an average of one liter of volume from their affected legs, their skin thickness and scarring eased, and they reported better quality of life. Holbreich reports similar alleviation of his symptoms — his leg appears smaller and the skin feels more supple, he said.
Rockson also led a placebo-controlled, phase 2 trial testing acebilustat for patients with upper-limb lymphedema; analysis of those results is underway. If the results mirror those of the lower limb trial, the researchers’ next step will be to launch an international, phase 3 trial designed to gain U.S. Food and Drug Administration approval of acebilustat.
Patients in these two trials took the drug while continuing physical therapy and at-home management of their condition, but Rockson is hopeful that, one day, medication alone could suffice.
“We hope that, ultimately, effective pharmacologic therapy could supplant physical self-care. There could even be a role for disease prevention in high-risk patients.” he said. “We hope that, if we can carry this work forward, it’s going to make a major impact.”
Researchers from Celltaxis, Inc. and the VA Palo Alto Health Care System contributed to the study.
The study was funded by the Stanford Innovative Medicines Accelerator program and Celltaxis Inc.
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Scientific Reports
Randomized controlled/clinical trial
People
Therapeutic selective leukotriene b4 antagonism for human lymphedema
15-Aug-2026