A first-of-its-kind treatment for mastocytosis

Seeking to understand the long term impact and safety of the drug avapritinib on treating patients with indolent systemic mastocytosis, a new study confirms the drug isn’t only safe, but also effective and well tolerated.

According to the Centers for Disease Control, mastocytosis is a disorder that occurs when too many mast cells accumulate in the skin and/or internal organs.

Most patients experience symptoms related to mediators released from activated mast cells.

Mast cells are a type of white blood cell in the immune system responsible for protecting the body from infection and releasing chemicals to neutralize toxins and create inflammatory responses.

“Patients with mastocytosis can present with very severe symptoms, similar to that of allergic type symptoms, such as flushing, itching, passing out, stomach issues,” explained Cem Akin, M.D., an allergy and immunologist at Michigan Medicine.

“And if a patient has bee, wasp, drug or food allergies on top of mastocytosis, it can be potentially life threatening because it maximizes their reaction,” said Akin, a leading expert in this particular area and first author on the new paper.

It’s a chronic illness which patients have needed to manage on their own along with their health physicians.

“Medications used before this one were over the counter antihistamines like cetirizine, diphenhydramine, etc., mainly as symptom directed therapy. But they didn’t do anything for the underlying mast cell burden taking place.”

Akin says this newer drug, called avapritinib, is specifically targeting an inhibitor of the most common mutation causing this disease and is the first drug for this non-advanced variety of mastocytosis based on a study called PIONEER, which Michigan Medicine was a major part of.

“The primary outcome was symptom improvement at the end of 6 months vs the placebo. Then when the placebo population switched over at end of six months, they too also showed improvements to the other group who improved,” said Akin.

But as with any chronic disease, clinicians still needed to know if avapritinib was safe long term – not just for six months.

The findings

Published in the Journal of Allergy Clinical Immunology, the group found several positive findings on the longer use of avapritinib on indolent systemic mastocytosis.

“First, efficacy was sustained over the three year follow up. This was important because it’s a hematologic neoplastic disorder – meaning other similar types of diseases are known to develop resistance to similar drugs leading to disease recurrence, but this didn’t happen,” said Akin.

Also, the safety remained unchanged.

“Side effects were the same with no life threatening safety issues.”

In addition to those findings, a characteristic of the disease is that people develop hundreds of brown spots on their skin that can feel physically and socially uncomfortable.

The drug was shown to improve that symptom as well.

In clinic, Akin says patients would question using the drug given its warnings and precautions in the FDA label for treating an advanced variant of the disease which often presents with leukemia or pre-leukemia.

But luckily, in this indolent setting, there’s less worry.

“When used for advanced systemic mastocytosis, doctors give 200 mg, which is a high dose and has safety concerns, such as brain bleeds if a patient also has low blood platelets. But here, we start with 25 mg.”

Another worry was that of cognitive changes, since the drug crosses the blood-brain barrier.

But none of these side effects were seen in the low dose trial they studied.

Additional reporting found a subset of patients at 25 mg, who were escalated to 50 mg at the discretion of their site investigator, also had the same favorable results.

What’s next?

It remains unclear about the long term impacts of avapritinib on pregnancy and fertility, which Akin says will be important to keep in mind.

Akin says they’ll also want to study osteoporosis more closely, as one in three patients often also have this issue.

Other investigational drugs could be approved in coming years, but for now, this is a huge advancement in the field.

“These findings are exciting as they herald a new era in cause directed and potentially disease modifying therapy of non-advanced mastocytosis, and the experience gained in depleting mast cells in mastocytosis can be extrapolated to other more common allergic and atopic diseases mediated by mast cell activation.”

Additional authors: Vito Sabato, Jason Gotlib, Jens Panse, Iván Álvarez-Twose, Deepti H Radia, Cristina Bulai Livideanu, Joseph Jurcic, Hanneke Oude Elberink, Paul Van Daele, Sonia Cerquozzi, Ingunn Dybedal, Andreas Reiter, Thanai Pongdee, Stéphane Barete, Celalettin Ustun, Philippe Schafhausen, Peter Vadas, Prithviraj Bose, Daniel J DeAngelo, Lindsay Rein, Pankit Vachhani, Massimo Triggiani, Patrizia Bonadonna, Karin Hartmann, Sigurd Broesby-Olsen, Mattias Mattsson, Tracy I George, William Shomali, Matthew Giannetti, Frank Siebenhaar, Hui-Min Lin, Ilda Bidollari, Benjamin Lampson, Janet Hong, Ashley Doyle, Tsewang Tashi, Mariana Castells

Funding/disclosures: Akin received research support and has a consultancy agreement with Blueprint Medicines, maker of avapritinib.

Tech transfer(s)/Conflict(s) of interest: In addition, Akin has research support and consultancy with Cogent which has an investigational tyrosine kinase inhibitor for use in mastocytosis.

Michigan Research Core(s): CTSU

Paper cited: “Avapritinib achieves long-term disease control with favorable safety in patients with indolent systemic mastocytosis over 3 years,” J Allergy Clin Immunol. DOI: 10.1016/j.jaci.2026.04.001

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