Avapritinib achieves long-term disease control with favorable safety in patients with indolent systemic mastocytosis over 3 years

BACKGROUND: Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE: We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS: The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus best supportive care in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS: As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a long-term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS: Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.

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Journal
Journal of Allergy and Clinical Immunology
Published
2026-04-01
DOI
https://doi.org/10.1016/j.jaci.2026.04.001
Primary Topic
Mast cells and histamine
Type
article
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article

Avapritinib achieves long-term disease control with favorable safety in patients with indolent systemic mastocytosis over 3 years

Matthew P. Giannetti, Mattias Mattsson, Sonia Cerquozzi, Pankit J. Vachhani et al.
Journal of Allergy and Clinical Immunology
Mast cells and histamine
article

Avapritinib achieves long-term disease control with favorable safety in patients with indolent systemic mastocytosis over 3 years

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

Abstract

BACKGROUND: Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE: We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS: The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus best supportive care in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS: As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a long-term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS: Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.

Journal of Allergy and Clinical Immunology
Oslo University Hospital (NO), Brigham and Women's Hospital (US), Rush University Medical Center (US), St. Michael's Hospital (CA), University of Salerno (IT), Mayo Clinic (US), University Medical Center Groningen (NL), Uppsala University Hospital (SE), The University of Texas MD Anderson Cancer Center (US), Universität Hamburg (DE), University of Calgary (CA), Duke University (US), Université Fédérale de Toulouse Midi-Pyrénées (FR), Guy's and St Thomas' NHS Foundation Trust (GB), University of Utah (US), Heidelberg University (DE), University of Michigan (US), Columbia University Irving Medical Center (US), Huntsman Cancer Institute (US), Odense University Hospital (DK), Erasmus MC (NL), University Hospital Heidelberg (DE), University Hospital of Basel (CH), University of Alabama at Birmingham (US), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Düsseldorf University Hospital (DE), Azienda Ospedaliera Universitaria Integrata Verona (IT), Hospital Virgen del Valle (ES), Assistance Publique – Hôpitaux de Paris (FR), Blueprint Medicines (United States) (US), Antwerp University Hospital (BE), University Medical Center Hamburg-Eppendorf (DE), Dana-Farber Cancer Institute (US), Universitätsklinikum Aachen (DE), Pitié-Salpêtrière Hospital (FR), Department of Biomedicine Basel (CH), Stanford Medicine (US), Mayo Clinic in Florida (US), University Medical Centre Mannheim (DE), Heinrich Heine University Düsseldorf (DE), RWTH Aachen University (DE), Erasmus University Rotterdam (NL), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 24%
Mast cells and histamine
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