Cem Akin, MD 

The Clinical Significance of a Durable Treatment for Indolent Systemic Mastocytosis

The Clinical Significance of Durable Treatment Response in ISM Management

The long-term data from avapritinib studies demonstrates remarkable durability of treatment response, with very few patients discontinuing therapy due to adverse events or lack of efficacy. This high retention rate serves as a strong indicator of the drug's effectiveness and patient satisfaction, suggesting that when patients begin treatment, they experience meaningful symptom improvement that motivates continued use. The sustained response over extended periods represents a significant advancement in indolent systemic mastocytosis (ISM) management, offering patients a treatment option that provides consistent relief from their chronic symptoms rather than temporary improvement.

The introduction of tyrosine kinase inhibitors represents a paradigm shift in ISM treatment, marking these medications as "new kids on the block" compared with traditional antihistamine therapies, many of which are available over the counter. This novelty has understandably created some prescriber hesitancy, as clinicians appropriately exercise caution when adopting new therapeutic agents, particularly for chronic conditions like ISM. Given that ISM patients typically have normal life expectancy compared to age-matched populations, any prescribed medication must demonstrate an exceptionally strong safety profile to justify long-term use. The comprehensive safety data emerging from extended follow-up studies addresses these concerns by providing reassurance about the drug's tolerability over multiple years.

The robust long-term safety and efficacy data has important implications for clinical practice patterns and patient access to treatment. Initially, when avapritinib first became available, there was a tendency to refer patients to specialized mastocytosis centers for evaluation and treatment initiation. However, with the emergence of comprehensive safety data extending up to 5 years, community allergists, immunologists, and other health care providers caring for ISM patients are expected to feel more comfortable prescribing this therapy in their practices. This shift toward broader prescribing comfort should improve patient access to effective treatment and reduce barriers to care, ultimately benefiting more patients with this challenging chronic condition.

Videos

A panelist discusses how the durability and safety of avapritinib over several years support its long-term use in indolent systemic mastocytosis, potentially increasing confidence among community providers to prescribe it beyond specialized centers.

Candidates for Consideration: Who Would Benefit from Avapritinib?

Identifying Appropriate Candidates for Avapritinib Therapy in ISM

The long-term safety data from the PIONEER trial provides reassuring evidence for avapritinib's tolerability profile, with major adverse events limited to peripheral and periorbital edema. Importantly, the safety concerns observed in advanced mastocytosis trials using higher doses (200 mg) were not replicated in the indolent systemic mastocytosis (ISM) population receiving 25-mg dosing. The concerning signals from high-dose studies, including intracranial bleeding in patients with low platelet counts and neurocognitive changes, were absent in the PIONEER long-term follow-up data. This favorable safety profile supports the consideration of avapritinib for appropriate ISM patients who remain symptomatic despite standard treatments.

Patient selection requires careful evaluation of contraindications and risk factors. Absolute contraindications include platelet counts below 50,000 (as specified in FDA labeling due to intracranial bleeding risk) and pregnancy (due to teratogenic potential of tyrosine kinase inhibitors). Additional relative contraindications that many providers consider include prior history of intracranial bleeding, stroke, brain lesions, or current anticoagulant therapy, as these factors may increase bleeding risk. These exclusions help ensure that avapritinib is prescribed to patients who can safely benefit from therapy while minimizing potential complications.

Ideal candidates for avapritinib therapy are patients with chronic, moderate to severe ISM symptoms who require daily antihistamine or antimediator treatments yet continue experiencing breakthrough symptoms such as flushing, itching, and abdominal pain. The decision-making process should involve mutual discussion between health care providers and patients, particularly when standard treatments cause problematic adverse effects or drug interactions. For example, antihistamines can interfere with calcium absorption, potentially exacerbating the baseline osteoporosis risk in ISM patients. Following appropriate patient selection and shared decision-making, treatment typically begins with 25 mg dosing, with monitoring for response and potential dose escalation to 50 mg if symptoms remain inadequately controlled.

A panelist discusses how appropriate candidates for avapritinib include patients with moderate to severe indolent systemic mastocytosis who remain symptomatic despite standard therapies, while those with low platelet counts, pregnancy, bleeding risks, or certain comorbidities should be excluded through shared decision-making.

Inside PIONEER: 3-Year Long-Term Safety and Efficacy Study of Avapritinib

The PIONEER Trial: Comprehensive Long-Term Evaluation of Avapritinib in ISM

The PIONEER trial was designed as a comprehensive 3-part study to evaluate avapritinib's safety and efficacy in treating indolent systemic mastocytosis (ISM). The first part functioned as a dose-finding trial, comparing 25 mg, 50 mg, and 100 mg doses against placebo in a small patient population. All tested doses demonstrated effectiveness, leading to the selection of 25 mg as the optimal moving-forward dose. The second part, a placebo-controlled study of the 25 mg dose, was published in the 

 in 2023 and formed the foundation for FDA approval. This pivotal study demonstrated superiority over placebo in both symptom control and reduction of objective disease markers, including tryptase levels, bone marrow mast cell burden, and 

 D816V mutation burden, making avapritinib the only tyrosine kinase inhibitor currently approved for ISM treatment.

The third part of PIONEER provided crucial long-term data through an open-label extension where all patients received 25 mg avapritinib, with some patients followed for up to 5 years and a median follow-up of 3 years. Patients experiencing suboptimal symptom control or inadequate reduction in disease markers could escalate to 50 mg dosing. Efficacy was measured using the Total Symptom Score (TSS), a composite assessment ranging from 0 to 110 that evaluated multiple organ systems including skin, gastrointestinal, and neurocognitive symptoms. The average patient baseline TSS was approximately 50, indicating moderate symptom burden. Quality of life was assessed separately using validated questionnaires to provide comprehensive outcome measures.

The long-term results demonstrated sustained and improving efficacy over time. While the initial 24-week data showed an average 15-point TSS reduction, extended follow-up revealed stable or enhanced benefits, with 17.5-point improvement at 96 weeks and 20-point improvement at 144 weeks. Among patients escalated to 50 mg, 41 out of 44 experienced stable to improved symptom control within similar ranges. Safety profiles remained favorable throughout the extended observation period, with hair loss and periorbital edema being the most common adverse effects, typically grade one in severity. Remarkably, only 3% of patients in the 25 mg cohort discontinued treatment due to adverse events, with no discontinuations in the 50 mg group, demonstrating excellent long-term tolerability.

A panelist discusses how the three part PIONEER study shows that avapritinib 25 mg (with optional escalation to 50 mg) sustains meaningful symptom and quality of life improvements with a favorable safety profile for up to five years, supporting its FDA approval for indolent systemic mastocytosis.

The Importance of Long-Term Safety and Efficacy Data for Treatments of Indolent Systemic Mastocytosis  

The Critical Need for Long-Term Safety and Efficacy Data in ISM Treatment

The chronic nature of indolent systemic mastocytosis (ISM) necessitates a comprehensive understanding of long-term treatment outcomes, as patients may require therapeutic interventions for many years or potentially lifelong. Given that ISM is a persistent condition with no current curative options, any medication that demonstrates meaningful impact on symptoms and quality of life must be evaluated not only for immediate efficacy but also for sustained safety over extended periods. This long-term perspective is crucial for both patients and health care providers when making treatment decisions that may span decades.

The importance of robust long-term data becomes evident when considering the treatment landscape for ISM. While medications may show promising results in short-term clinical trials, the real-world application requires assurance that benefits persist and adverse effects remain manageable over years of continuous use. The original clinical trial data, published in the 

, demonstrated superiority over placebo at the 24-week follow-up timeframe, establishing initial proof of concept for targeted therapy approaches in ISM treatment.

Extended follow-up studies provide invaluable insights that bridge the gap between clinical trial efficacy and real-world clinical practice. Current research examining patients over extended periods, with median follow-up reaching three years and some patients followed for up to five years, offers reassuring data for health care providers managing ISM patients who remain refractory to standard first-line treatments. This long-term safety and efficacy information serves as a crucial discussion guide for clinical decision-making, helping determine patient candidacy for advanced therapeutic options and providing confidence in treatment recommendations that may extend over many years of patient care.

A panelist discusses how long-term safety and efficacy data are essential for treating indolent systemic mastocytosis, given its chronic nature and the potential need for lifelong therapy, with recent findings supporting the sustained benefits of avapritinib.

Cem Akin, MD

Articles