Quest to find better treatments for rare blood cancer leads to new therapies

In 2015, Sally Worthen developed a persistent, itchy rash on her thighs and torso. An active equestrian, the Southern California resident didn’t think much of it at first. “I went to see a couple of dermatologists, who asked whether I’d changed laundry detergents or skin care products,” Worthen, 69, recalled.

A dermatologist who took a sample of one of the welts referred her to a local hematologist, who ordered a bone marrow biopsy and further laboratory studies. Soon Worthen received a phone call from the doctor.

“She was so upset,” Worthen said.

Worthen had advanced systemic mastocytosis (SM) — a rare but deadly blood cancer with a life expectancy of less than a few years. But she didn’t feel ill.

A search for treatment options

“At that time, there was no FDA-approved treatment for patients with Sally’s form of the disease,” Worthen’s husband, Bill, a medical products specialist, recalled, using an abbreviation for the Food and Drug Administration. The only treatment was chemotherapy, which they were reluctant to pursue while Sally Worthen was feeling well. Instead, the couple devoted themselves to researching other options.

They learned about an international phase-2 clinical trial of a drug called midostaurin for people with advanced SM.

Jason Gotlib, MD, professor of hematology at Stanford Medicine, was overseeing the trial.

Advanced SM is caused by a proliferation of a white blood cell called a mast cell that can be found in several organs, including the bone marrow, spleen, liver, gastrointestinal tract, lymph nodes, and skin. Mast cells secrete numerous molecules, including histamine and tryptase, that mediate the body’s allergic and inflammatory responses. Mastocytosis can be cutaneous — confined to the skin — or systemic, in which multiple organs are affected.

Patients with SM can experience flushing, itching, diarrhea and, in some cases, life-threatening anaphylaxis. In advanced forms of the disease, the infiltration of organs by mast cells leads to signs of organ damage, such as low blood counts, liver-function abnormalities, malabsorption with weight loss, and bone fractures.

The disease progresses

When Worthen first visited Gotlib at Stanford in early 2017, she was no longer feeling well. She was very fatigued and had an extensive, diffuse rash. She had lost weight and was experiencing severe gastrointestinal side effects and an enlarged spleen from the disease.

“Overall, her quality of life was quite poor,” Gotlib said. Worthen’s tryptase level — a marker of disease severity — was over 600; normal is 11.5 or less.

About 95% of cases of advanced SM are caused by a mutation in a protein called KIT that drives the proliferation of mast cells. KIT belongs to a family of proteins called tyrosine kinases. The mutation, called D816V, causes the KIT protein to be always on, signaling to the mast cells to keep dividing.

Although a medication called imatinib, which is sold under the brand name Gleevec, has been approved for use in advanced SM, it is ineffective against the D816V mutation (although it may be useful in the rare SM patients who have normal KIT or other mutations in the gene).

Gotlib suggested Worthen enroll in a phase-1 clinical trial he was leading of a drug called avapritinib, which has a mechanism of action similar to midostaurin’s but is less likely to cause severe side effects because it targets only the KIT protein. Although the trial was designed primarily to test the safety of avapritinib and determine the best dose for patients, Worthen was eager to participate.

“Sally had lost 20 pounds; she couldn’t keep any food down,” Bill Worthen said. “We said we would do anything. It was either try this, or die.”

“Avapritinib is considerably more selective than midostaurin,” Gotlib said. “It was specifically designed to inhibit the KIT D816V mutation with very few other targets. Midostaurin was a big step forward in the treatment of advanced SM, but it hits several other targets, and avapritinib is more potent.”

Sally Worthen experienced a dramatic change when she enrolled in the avapritinib trial, known as EXPLORER. “Within months, her tryptase levels had dropped like a rock,” her husband said. “Her welts started to disappear, and she was able to start eating again.” Worthen’s bone marrow biopsies showed rapidly decreasing numbers of mast cells, and her spleen began to shrink.

“I couldn’t believe it; it was like a miracle,” she said.

“Sally was similar to other patients who experienced dramatic improvements,” Gotlib said. “Together they painted a picture of how effective this drug is.”

Of the 53 patients with advanced SM evaluated in the EXPLORER trial, 75% experienced at least some benefit from the drug and 36% of patients experienced a complete remission. The drug is not without side effects, which may include facial swelling, diarrhea, nausea and fatigue. There is also a risk of intracranial bleeding in people with low platelet counts.

The interim results of a subsequent, ongoing phase-2 clinical trial, called the PATHFINDER trial, led to the approval of avapritinib by the FDA in June of 2021. Findings from both trials were published simultaneously in Nature Medicine in December. Gotlib was the senior and lead author of both papers.

“We now have two drugs approved for the front-line treatment of advanced SM,” Gotlib said. “This is a really beautiful example of the effectiveness of targeted therapy for a rare disease, and I’m delighted to see how it has improved the lives of these patients.”

The treatment allowed Worthen to get her life back, including a return to horseback riding. She now relies on regular blood tests to ensure her disease has not returned. “Slowly I got stronger, and I’m now feeling back to where I was before I became ill,” she said. “I feel very, very lucky and thankful.”

The trials were funded by Blueprint Medicines Corp., which markets avapritinib under the trade name Ayvakit. Gotlib has received research and travel funding from Blueprint Medicines and has served on advisory boards for the company.

The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children’s Health. For information about all three, please visit http://med.stanford.edu.