Avapritinib versus Placebo in Indolent Systemic Mastocytosis

Paul van Daele, Jason Gotlib*, Mariana Castells, J. Hanneke N.G. Oude Elberink, Frank Siebenhaar, Karin Hartmann, Sigurd Broesby-Olsen, Tracy I. George, Jens Panse, I Alvarez-Twose, Deepti H. Radia, Tsewang Tashi, Cristina Bulai Livideanu, Vito Sabato, Mark Heaney, Paul van Daele, Sonia Cerquozzi, Ingunn Dybedal, Andreas Reiter, Thanai PongdeeStephane Barete, Celalettin Ustun, Lawrence Schwarts, Brant R. Ward, Philippe Schafhausen, Peter Vadas, Prithviraj Bose, Daniel J. DeAngelo, Lindsay Rein, Pankit Vachhani, Massimo Triggiani, Patrizia Bonadonna, Mark Rafferty, Nauman M. Butt, Stephen T. Oh, Friederike Wortmann, Johanna Ungerstedt, Mar Guilarte, Minakshi Taparia, Andrew T. Kuykendall, Cecilia Arana Yi, Princess Ogbugo, Caroline Gaudy-Marqueste, Mattias Mattson, William Shomali, Matthew P. Giannetti, Ilda Bidollari, Hui-Min Lin, Erin Sullivan, Brenton Mar, Robyn Scherber, Maria Roche, Cem Akin, Marcus Maurer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM.

We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures.

From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events.

In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)
Original languageEnglish
JournalNew England Journal of Medicine
Issue number6
Publication statusPublished - 23 May 2023

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