If you were diagnosed with systemic mastocytosis just 10 years ago, treatment usually meant a one-size-fits-all approach that focused on managing symptoms instead of tackling the root cause. For some people, that meant taking several medications — sometimes as many as eight — multiple times each day.
There’s still no cure, but in recent years the FDA has approved new drugs, with others in the works, that target the disease more precisely and deliver better results for people with different forms of the condition.
Lindsay Rein, MD, associate professor of medicine at the Duke University School of Medicine in Durham, North Carolina, says that today’s treatment options address what’s driving the biology of systemic mastocytosis.
“We’re getting to the point where we’re modifying the disease,” she says. “From a patient perspective, it’s incredible.”
A New Generation of Drugs
Most people with systemic mastocytosis — over 80% — have a mutation or change in their KIT gene. This gene controls how certain cells develop, including mast cells, which are part of your immune system and release chemicals like histamine when they detect a threat. In systemic mastocytosis, your body makes too many mast cells.
For milder cases, doctors usually recommend antihistamines to block these chemicals and help ease symptoms. But since 2017, they’ve been able to prescribe new drugs that directly target the faulty KIT receptor, essentially switching off the signal that causes mast cells to multiply.
Midostaurin (Rydapt). The first KIT inhibitor approved by the FDA was a drug called midostaurin for adults with aggressive forms of systemic mastocytosis. In phase 2 clinical trials, 60% of people responded to the drug, with about half having at least one type of organ damage caused by the condition completely resolved. On average, the number of mast cells in bone marrow also dropped by about 60%. Levels of tryptase — a key marker of mast cell activity — fell by a similar amount.
While midostaurin’s approval marked a major breakthrough in treating systemic mastocytosis, the drug also has some downsides. It can improve some symptoms, like skin changes, but can also cause new ones. More than 20% of people who take midostaurin have nausea, vomiting, diarrhea, muscle pain, fatigue, or infections.
Avapritinib (Ayvakit). In 2021, the FDA approved another KIT inhibitor, avapritinib, for advanced systemic mastocytosis. Two years later, in 2023, it was also approved as the first treatment for people with indolent systemic mastocytosis (ISM) — the most common type, affecting about 90% of systemic mastocytosis cases. Like midostaurin, avapritinib can lower the number of mast cells and help prevent organ damage , but it also improves overall symptoms, including brain fog, gastrointestinal symptoms, joint pain, and skin rashes. Some research suggests it may help protect bone density, too — which is important, since osteoporosis is a common complication in systemic mastocytosis.
Mariana Castells, MD, PhD, director of the Mastocytosis Center at Brigham and Women’s Hospital and a professor at Harvard Medical School, says many people who switch to avapritinib are able to gradually stop taking many of the medications they had relied on to manage symptoms.
“When patients have to take a lot of medications to be able to improve their quality of life … it impacts them,” she says. “They might have to set timers every day to remind them when to take medications, or maybe they have to worry about interactions.”
That’s no longer the case.
Bezuclastinib. Over the next few years, more KIT-inhibiting drugs are likely to reach people with systemic mastocytosis. Of those drugs, bezuclastinib is the furthest along. It was developed to better target the mutation that causes systemic mastocytosis. But what sets it apart from other KIT-inhibitors is that it doesn’t cross the blood-brain barrier. That means it won’t cause some of the cognitive side effects — like mood changes or insomnia — linked to avapritinib and midostaurin. In an early study, nearly 90% of people who took bezuclastinib saw their mast cells drop by at least half. Researchers expect it could be approved as early as 2026.
“These inhibitors keep getting better,” Rein says. “They’re becoming more tolerable and with an improved safety profile for patients.”
Elenestinib. The same pharmaceutical company that makes avapritinib has another KIT-inhibitor in the works called elenestinib. Like bezuclastinib, it’s expected to cause fewer side-effects because it doesn’t cross the blood-brain barrier. In an early clinical trial for ISM, all patients who took the drug for 12 weeks saw improvement in at least some of their symptoms and had lower levels of active mast cells.
Expanding the Treatment Toolbox
Researchers are also studying a newer class of drugs called Bruton tyrosine kinase (BTK) for systemic mastocytosis. Instead of targeting the genetic mutation that causes mast cells to multiply, BTK inhibitors can block the signals that tell mast cells to release their chemical contents, including histamine. By stopping this pathway, these drugs may help lower many of the disease’s symptoms. Researchers are excited about this approach because it targets the disease from a different angle.
Cem Akin, MD, clinical professor of internal medicine at the University of Michigan Health in Ann Arbor, Michigan, sees potential in BTK inhibitors as a promising addition to existing treatment options.
“No single treatment is effective in 100% of patients,” he says. “In five to 10 years, these could be a combination treatment with a KIT-inhibitor, another inhibitor or another signal translation that might be on the horizon.”
BTK inhibitors are already approved for other diseases, including blood cancers and some autoimmune disorders, but they’re still being tested for systemic mastocytosis. The drug TL-895 is in active clinical trials.
Finding the Right Care and Support
Living with a rare disease like systemic mastocytosis can be challenging — not just because of the symptoms, but also because fewer doctors know how to treat it and there’s less information readily available. That’s why Rein encourages people to try to find a center of excellence, where specialists have more experience with the condition.
Treating systemic mastocytosis is a team sport, Rein says.
“You’re going to need more than one person on your team,” she says.
Often an allergist, along with specialists in mental health, gastroenterology, and dermatology. The American Initiative in Mast Cell Diseases (AIM), which lists experts and treatment centers — can be a helpful place to start along with patient advocacy and support groups.
Some people with systemic mastocytosis might also consider joining a clinical trial to access new treatments sooner. While Rein says clinical trials may not be right for everyone, it’s still a good idea to explore your options.
“It's kind of a double-edged sword. There’s increased monitoring, which can be great for some people but not right for others,” she says. “At the very least, I tell everyone to at least get the information, learn what’s available, and if it’s not for you, that’s OK, but then you at least feel comfortable in knowing that you had all the information and made the best decision.”
Imagining a Different Future
Looking ahead, the outlook for systemic mastocytosis is far better than it once was. Experts see a future that includes more targeted medications with fewer side effects, smarter combination therapies and, further down the road, approaches that could possibly modify or even get rid of the disease using emerging technologies like gene editing. That progress means not just better treatment, but a potentially different experience of living with systemic mastocytosis.
“I think what all this research has really brought is hope,” says Rein. “What we’ve seen with all of these therapies are improvements in the quality of life and ultimately, that’s probably the most important thing for patients … as a community, it’s been incredible to see all the progress, and I’m looking forward to seeing more progress over time.”
