Avapritinib Sustains Long-Term QoL Gains in ISM with Mariana C. Castells, MD, PhD

Credit: US Food and Drug Administration

Among individuals with indolent systemic mastocytosis (ISM) treated with avapritinib (AYVAKIT), symptom and quality of life improvements were sustained across >2 years of follow-up in the randomized PIONEER study.

In May 2023, the US Food and Drug Administration (FDA) approved avapritinib (AYVAKIT) for the treatment of adults with ISM, marking the first medicine designed to target KIT D816V, the primary underlying cause of the disease, and relieve the mast cell symptom burden.

Approximately 226 patients with inadequately controlled ISM despite best supportive care initiated 25 mg once-daily avapritinib in the extension portion of PIONEER, including 75 patients who initially received placebo and crossed over to active treatment. There were no new safety concerns identified with longer treatment exposure, with similar treatment-related adverse events, compared with the initial report.

At the 2025 American Academy of Allergy, Asthma, and Immunology (AAAAI)/World Allergy Organization (WAO) Joint Congress, Mariana C. Castells, MD, PhD, director of the drug hypersensitivity and drug desensitization center and the mastocytosis center at Brigham & Women’s Hospital, spoke with HCPLive on the impact of this long-term follow-up and the quality of life and safety benefit of avapritinib for ISM.

This transcript has been edited for clarity.

Based on these results indicating durable symptom and quality life improvement over 2 years, what showed the most significant benefit and how do these data translate to patient outcomes?

In Pioneer, the tryptase level, which is a reflection of the mast cell burden, went to an almost normal range for a majority of the patients. This is critically important. We also saw that the KIT D816V mutation also showed a dramatic decrease of 80% or more. The possibility of moving into a more aggressive disease is not happening, potentially because of those changes. The total symptom score also had a dramatic improvement, particularly because it was compared to placebo. When the placebo arm was switched to the active arm, the changes in the symptoms were very significant.

What do these safety results tell us about the long-term tolerability of avapritinib?

Patients included in the clinical trial were not under good control of their symptoms under the best standard medication. These patients who were already on 5–7 or more medications, antihistamines or leukotriene blockers, have been able to decrease the medications that they are taking, so that’s a pretty significant improvement. A minor side effect of edema around the eyes has been observed in Pioneer, but there were no major side effects in terms of any brain symptoms or the liver or kidney. The safety of the trial has been paramount.

Based on positive efficacy and safety results from Pioneer, what do you see as the next step in the treatment landscape for ISM?

Patients included in the trials did not have optimal control of their disease, despite being on all those medications. We have started to put patients with mastocytosis under avapritinib, which is FDA-approved now, and we are seeing in real life what is happening. There are two complications of mastocytosis, one being anaphylaxis.

At least one-third of these patients come to us because they have a severe anaphylactic event and the tryptase is done. Then, after the event, another tryptase and that tryptase is elevated the baseline tryptase. It’s found that those patients have a KIT mutation in the peripheral blood and they have a bone marrow ordered and ultimately, a diagnosis of mastocytosis.

For those patients having fewer anaphylactic events, not using their epinephrine device, or not going to the emergency room, it’s protection and safety we had not seen before with any other medication, except for maybe Anti-immunoglobulin (anti-IG). Omalizumab (XOLAIR), which is anti-IG, had been used for that. Targeting the amount of mast cells might be a better way to do this.

On the other hand, there’s also a bone impact. Of the patients with mastocytosis, one-third of them will have osteopenia or osteoporosis. They had bone loss because mast cells release mediators that chew up the bones. For those patients, particularly women in premenopausal ages, where they can also break their bones, having fewer mast cells will potentially protect their bones. Those two effects are not part of the trials that are ongoing but may represent important quality-of-life factors in real life.

Castells reports relevant disclosures with Blueprint Medicines, Cogent Biosciences, and Telios Pharmaceuticals.

References

1. Castells M, Akin C, Maurer M, et al. Long-term Quality of Life and Safety in Patients with Indolent Systemic Mastocytosis Treated with Avapritinib in the PIONEER Study. Presented at: 2025 AAAAI/WAO Joint Congress, February 28-March 3. Abstract 534

2. FDA approves AYVAKIT® (avapritinib) as the first and only treatment for indolent systemic mastocytosis. Blueprint Medicines Corp. May 22, 2023. Accessed March 3, 2025. https://ir.blueprintmedicines.com/news-releases/news-release-details/fda-approves-ayvakitr-avapritinib-first-and-only-treatment.