Valerie Slee
Valerie Slee poses for a family picture with her husband, Andrew, and their four grandsons. (Photo courtesy of Valerie Slee)

NEW ORLEANS, La.—Valerie Slee was a 34-year-old pediatric nurse living in Pennsylvania in 1987 when she was diagnosed with the disease that would come to frustrate her life.

Since the age of 6, Slee had suffered abdominal pain, bloating, nausea, diarrhea, and constant itching without knowing why. “I was totally insensitive to any kind of heat, and there was a 2-year period where I would break out in hives,” she said.

Finally, during a 1997 gastrointestinal exam in Philadelphia, Pennsylvania, Slee’s doctor noticed his patient’s facial flushing and quickly determined she had systemic mastocytosis (SM).

“The prognosis for SM was very poor then. Everything I read about the disease said I had 2 to 3 years to live, so I was panic-stricken,” Slee, 69, told Rare Disease Advisor. “It wasn’t until later on that scientists had a better idea of the normal course of SM. Now, patients for the most part can expect a near normal life expectancy.”

In 2002, the diagnostic criteria for SM were established for the first time, and Slee did not fulfill those criteria. Her diagnosis was changed to mast cell activation syndrome (MCAS), in which patients have similar symptoms as SM but without a clonal mutation such as KIT D816V.

As her health declined, Slee and her husband, Andrew, moved to the Boston, Massachusetts, area where she could receive more specialized care.

“I take almost 100 pills a day, and my sweet husband counts them out for me and puts them in containers. That’s what I need to take to stay alive,” Slee said, explaining that the gradual disintegration of her vertebral column causes terrible back pain. “My quality of life is fair. I would love to say it’s better than that, but I’m symptomatic every day.”

She added: “The most challenging aspect of having a mast cell disease is the unpredictable onset of totally disabling symptoms.“

Slee served from 2009 to 2022 as chair of The Mast Cell Disease Society (TMS), a nonprofit patient advocacy organization based in Sterling, Massachusetts. In early 2023, Slee handed over leadership of TMS to Judith Emmel but plans to remain chair emeritus of its board of directors, as well as an active member of its research committee.

TMS, established in 1995, today serves a network of more than 20,000 patients, and awards grants in conjunction with the American Academy of Allergy, Asthma and Immunology (AAAAI). It also funds research in collaboration with other groups such as the Ehlers-Danlos Society.

“We have a new goal of increasing how much of our budget is allocated to research grants over the next few years in addition to funding educational and patient-family support programs,” Slee said. Since 2018, TMS has awarded roughly $360,000 in research grants.

Average SM Diagnosis Takes 7 Years

At least 200,000 Americans are thought to have systemic mastocytosis, according to Slee, though the actual number is likely higher due to better diagnosis and greater recognition of the disease.

Çem Akin, MD, a clinical professor at University of Michigan Health in Ann Arbor, at the ASH 2022 conference in New Orleans, Louisiana. (Photo by Larry Luxner)

Turkish hematologist Çem Akin, MD, a clinical professor at the University of Michigan Health in Ann Arbor, is an expert in systemic mastocytosis, as well as a specialist in allergy and immunology.

Dr. Akin got interested in mastocytosis because when he began his fellowship at the National Institutes of Health (NIH) in Bethesda, Maryland, his mentor—Dean Metcalfe, MD, MS, of the NIH’s National Institute of Allergy and Infectious Diseases—had just helped identify the KIT D816V mutation and its role in SM.

“My project was to look at different cell lineages to see if there’s multilineage involvement,” he said. “Although I was doing an allergy fellowship, I was very intimately involved with hematologic aspects of mast cell development. As mast cells are involved in allergic disorders, we have a vested interest as allergists to understand more about how they grow, differentiate, and get activated.”

In an interview at the 64th ASH Annual Meeting and Exposition here, he said SM is a very complicated disease, affecting roughly 1 in 10,000 people.

“Of course, that may be an underestimate to a certain extent because of underdiagnosis,” he said. “About 40% of patients are children. They almost always present with skin lesions. When you see the skin lesions—most of them are born with it or developed it within the first 6 months— there’s usually no doubt about the diagnosis.”

But 20%-30% of people with SM lack skin lesions and therefore have no visible signs of disease.

“These patients present with symptoms of allergic diseases like flushing, itching, stomach cramping, and so on,” Dr. Akin said, adding that they face significant delays in getting diagnosed properly. “The average delay in diagnosis from the onset of the symptoms is about 7 years. These patients, unfortunately, go from one specialist to the next until somebody finally thinks about checking mastocytosis.”

Rather Limited Treatment Options

Systemic mastocytosis broadly falls into 2 categories: advanced (malignant) and nonadvanced (benign), each of which is further divided into subgroups. Within the advanced group is a form of the disease called aggressive systemic mastocytosis, in which mast cells infiltrate into the bone marrow, skeletal system, liver, spleen, and gastrointestinal tract, reducing life expectancy.

Even more aggressive is mast cell leukemia, which has the shortest life expectancy, with a median survival of only 6 months after diagnosis.

On the other hand, about 70%-80% of patients with SM have the nonadvanced or benign form—most commonly indolent systemic mastocytosis—meaning they can expect a normal lifespan.

“It’s only shorter if they advance into one of the advanced categories, but that risk of advancement is about 3% overall. If they stay within the indolent group, their life expectancy is almost very, very close to their age-matched controls,” Dr. Akin said. “That doesn’t mean that their quality of life is as good as people without mastocytosis. Not having an advanced disease is not necessarily a walk in the park for these patients.”

That’s because SM patients often suffer the symptoms of mast cell activation, which include flushing, urticaria, diarrhea, skin lesions, abdominal cramping, and occasional unpredictable anaphylactic shock episodes.

“About 10% of people who have severe allergic reactions and pass out from bee stings may have underlying mastocytosis,” he said. “As we become more aware of those patients, we’ve built screening for mastocytosis into our allergy guidelines in evaluation of patients with bee sting or idiopathic anaphylaxis.”

For now, the US Food and Drug Administration (FDA) has approved only 2 therapies for SM: imatinib (Gleevec®) and midostaurin (Rydapt®), both developed by Novartis. Yet both have their drawbacks. Imatinib isn’t an option for the 90% of SM patients with the D816V KIT mutation, meaning very few such patients actually qualify for treatment with this drug.

Unlike imatinib, midostaurin inhibits both wild-type and D816V mutant KIT, meaning it’s more effective but also has more side effects, such as nausea and vomiting.

“While that may be acceptable for patients with advanced disease, it is often unacceptable to patients with indolent disease,” Dr. Akin said.

A third medication, avapritinib (Ayvakit) specifically targets the D816V KIT mutation but is FDA-approved for use in advanced disease only; it’s also used to treat unresectable or metastatic gastrointestinal stromal tumors (GISTs). Two others kinase inhibitors, BLU-263 and bezuclastinib, are undergoing clinical trials.

“At this time, none of these kinase inhibitors are FDA-approved for indolent disease,” Dr. Akin said, adding that he expects such approval to come in the next few years.