Mariana C. Castells, MD, PhD is the director of the drug hypersensitivity and drug desensitization center and the mastocytosis center at Brigham & Women’s Hospital.

Mariana C. Castells, MD, PhD

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

 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.

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 

 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.

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

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.

Articles

Avapritinib (AYVAKIT) has shown sustained improvements in symptoms and quality of life for individuals with indolent systemic mastocytosis (ISM) over more than two years, as demonstrated in the PIONEER study. The FDA approved avapritinib in May 2023, marking it as the first treatment targeting the KIT D816V mutation, the primary cause of ISM. The study revealed significant reductions in tryptase levels and KIT D816V mutation burden, with no new safety concerns. Avapritinib also reduced the need for additional medications and improved patient outcomes.

Castells discusses improvements in symptoms and quality of life scores for patients with indolent systemic mastocytosis across >2 years of the PIONEER trial.

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

 have long relied on symptom management rather than disease-modifying treatments. Now, emerging therapies targeting a key genetic mutation that drives abnormal mast cell growth are reshaping the treatment landscape, offering new hope for improved outcomes.

The ongoing randomized, double-blind, placebo-controlled, Phase 2/3 HARBOR trial is evaluating the efficacy and safety of oral elenestinib, a highly selective KIT D816V inhibitor with minimal brain penetration, for patients with ISM with symptoms inadequately controlled by best supportive care. Results from part 1 of the trial supported the tolerability and pharmacokinetics of once-daily dosing of elenestinib.

on what’s missing from the current treatment landscape, the potential implications of elenestinib, and part 2 of the ongoing Phase 2/3 trial.

From your clinical perspective, what’s missing from the current treatment landscape in ISM?

Essentially, what's missing is a medication that could take care of the mast cell burden. For example, the number of mast cells in the tissues, and also the activation of those mast cells. There are two components of mastocytosis. One is that the patients have too many mast cells in the skin. For example, they have a specific rash called urticaria pigmentosa or cutaneous mastocytosis. That’s also in children, which is an unmet need. We have no medication to get rid of those lesions.

Then, there is also the burden of those symptoms. Mast cells are cells of the immune system that have a lot of mediators, starting with tryptase, histamine, prostaglandins, and leukotrienes. They release those mediators, and those mediators go to the tissues and produce symptoms, including itching, flushing, abdominal bloating, pain, diarrhea, and brain fog. A lot of those symptoms, including fatigue, diminish the patient’s quality of life. We have up to now used antihistamines and medications directed towards symptom control, and we find that this might not be sufficient for two reasons.

One is that patients are on polypharmacy, so we need many antihistamines and other medications to block the effects of leukotrienes, prostaglandins, and so forth. On the other hand, those do not address the central problem and those medications may have side effects. They do not address the central problem of having too many mast cells, so the disease progresses and continues.

What are the mechanisms of action and clinical relevance of elenestinib for the treatment of ISM?

Elenestinib is part of the new generation of medications called tyrosine kinase inhibitors (TKIs). It doesn't cross the blood-brain barrier, and it addresses the 

 mutation which is a protein on the surface of the mast cells at the origin of mastocytosis in about 95% of the patients. It’s a targeted small molecule that addresses or targets this D816V-mutant KIT protein on top of the mutated mast cells, and that makes the muscles die. The important and interesting thing about this next generation is it doesn't cross the blood-brain barrier, so it doesn't have potential side effects on the central nervous system.

Based on the HARBOR trial, what stands out to you in terms of symptom improvement, biomarker changes, and drug safety?

We only have the first part, we haven't gone to part two of the elenestinib trial. In that first part, we have seen that the patients have a pretty significant improvement in the total symptom score (TSS). All the symptoms in all the organ systems seem to decrease in potentially a very significant way, whether it's the skin itching and flushing, the abdominal bloating, pain, and diarrhea, as well as the brain symptoms. That is quite significant and then we don't potentially have any other brain side effects that could happen with first generation of TKIs.

How vast are the implications of these data, and what could they mean for the treatment of patients with ISM in the near future?

We never dreamed of targeted medications for mastocytosis patients. It's a rare disease, and for a very long time, for the first 40 years of having a good understanding of its biology, we treated it symptomatically. We have now a tremendous opportunity to treat it in a way that is targeted, and it will make a significant and dramatic impact on the quality of life of those patients.

Castells M, Livideanu CB, Hermine O, et al. HARBOR: An Ongoing Phase 2/3 Study of Elenestinib in Patients With Indolent Systemic Mastocytosis. Presented at: 2025 AAAAI/WAO Joint Congress, February 28-March 3. Abstract 533

Indolent systemic mastocytosis (ISM) treatment is evolving with the approval of avapritinib, targeting the KIT D816V mutation, offering new hope for patients. The HARBOR trial is assessing elenestinib, another KIT D816V inhibitor, showing promise in symptom improvement and safety. Current treatments focus on symptom management, but emerging therapies aim to address the underlying mast cell burden. Elenestinib, a tyrosine kinase inhibitor, targets the KIT mutation without crossing the blood-brain barrier, potentially reducing central nervous system side effects and improving patient quality of life.

Castells describes what’s missing from the current treatment landscape and the potential implications of elenestinib for indolent systemic mastocytosis.