There is still no approved drug for lymphedema. A small Stanford Medicine trial suggests that could change, though the catch is that the study had no placebo group and the evidence is early.
The trial, led by Dr. Stanley Rockson, the Allan and Tina Neill Professor in Lymphatic Research and Medicine, gave an experimental oral drug called acebilustat once a day for a year to 23 volunteers with lymphedema of the lower limbs. The drug eased many of the disease’s most burdensome symptoms. Patients lost an average of one liter of volume from the affected legs, their skin thickness and scarring eased, and they reported a better quality of life. The results appeared in Scientific Reports. Rockson is senior author and Catharine Bowman, a PhD candidate in epidemiology and population health, is lead author.
What lymphedema is, and why current care falls short
Lymphedema is a condition in which excess lymph fluid builds up in an arm or leg instead of draining away. Rockson estimates that 10 million people in the U.S. have it, and likely hundreds of millions worldwide. As it advances, skin thickens and extra fat and scar tissue form beneath it. It can be painful and limit activity.
Causes include lymph node damage from radiation or surgery, notably for breast and gynecologic cancers, and conditions such as obesity, heart failure, sleep apnea and venous hypertension. Some cases appear to be genetic. Women are affected more often, partly because breast cancer is one of the risk factors.
Standard care means physical therapy, bulky compression garments and compression machines used for an hour or more every day. “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,” Rockson said. Insurers typically do not cover the treatments in full, so patients carry much of the cost.
Matthew Holbreich, one of the volunteers, knows the routine. He was a college senior when the swelling began in his left leg, and he was diagnosed with lymphedema 23 years ago. He wears a compression stocking daily, undergoes lymphatic massage and heavy wrapping twice a year, and has been hospitalized twice for infections, to which lymphedema patients are prone. He works for a clinical trial software company. After the trial he said his leg looks smaller and the skin feels more supple. “There’s currently no treatment for lymphedema other than wrapping,” he said. “It’s very antiquated.”
From ketoprofen to a narrower target
In the mid-1990s Rockson set out to test whether the late-stage tissue changes could be reversed. His lab built a mouse model and found that inflammation underlies the disease, with a group of molecules called the 5-lipoxygenase, or 5-LO, pathway playing a part. Two clinical trials then showed that ketoprofen, an anti-inflammatory that acts on this pathway, relieved symptoms. But long-term use of such drugs was later found to raise the risk of heart disease. “We didn’t want to trade a non-life-threatening disease for a life-threatening one,” Rockson said.
The team went back to the lab and identified a protein in the pathway, leukotriene B4 or LTB4, as responsible for ketoprofen’s benefit. Patients with lymphedema have higher than normal blood levels of it, and blocking it eased symptoms in mice. Acebilustat halts LTB4 production and seems to act only on the 5-LO pathway, whereas ketoprofen also hits other inflammatory systems.
What comes next
Rockson has also led a placebo-controlled phase 2 trial of acebilustat in upper-limb lymphedema, and analysis is underway. If those results mirror the lower-limb findings, the next step is an international phase 3 trial aimed at U.S. Food and Drug Administration approval. Volunteers in both trials kept up physical therapy and home care while taking the drug. Rockson hopes medication alone could one day be enough, and perhaps even prevent the disease in high-risk patients.
The study was funded by the Stanford Innovative Medicines Accelerator program and Celltaxis Inc., and researchers from Celltaxis and the VA Palo Alto Health Care System contributed.
