Introduction: Systemic mastocytosis (SM) is a hematologic neoplasm driven by the KIT D816V mutation in ~95% of cases. Avapritinib, a potent, selective inhibitor of KIT D816V, improves overall survival in advanced SM (AdvSM) and reduces disease-related symptoms in indolent SM (ISM), leading to its approval for treatment in both subtypes. In AdvSM, avapritinib treatment leads to the rapid and durable suppression of the KIT D816V mutation and is not associated with the development of on-target resistance mutations. In ISM, the impact of avapritinib on long-term clonal dynamics has not yet been evaluated. Here, we performed centralized droplet digital polymerase chain reaction (ddPCR) andnext-generation sequencing (NGS) on avapritinib-treated ISM patient samples from the PIONEER study (NCT03731260). This analysis provides, for the first time, an understanding of the dynamics of both KIT and non-KIT clonal mutations in the peripheral blood (PB) of patients with ISM receiving a selective KIT D816V inhibitor.

Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3) with up to 5 years of follow-up. All patients received avapritinib + best supportive care (BSC). Centralized ddPCR testing for the KIT D816V variant allele frequency (VAF) in the PB was performed at baseline and while on study using the ICON plc., Cambridge, MA, USA, assay (lower limit of detection [LOD]: 0.022%). Additional testing for mutations in 54 myeloid-malignancy related genes (including KIT exons 2, 8‒11, 13, and 17) was performed on banked PB samples from baseline and while on study using the Illumina® TruSight Myeloid NGS panel.

Results: A total of 245 patients with ISM received avapritinib treatment across Parts 1, 2, and/or 3 of the study and had ddPCR for KIT D816V VAF and NGS performed on the PB. The median (range)KIT D816V VAF at baseline was 0.34% (undetectable‒41.29%). Out of 154 patients who had detectable KIT D816V VAF in PB at baseline and who had KIT D816V VAF testing at 48 weeks of treatment, 151 (98%) patients experienced a decrease in KIT D816V VAF (median [range] VAF 0.13% [undetectable‒33.01%]), 102 (66%) experienced a ≥50% decrease in KIT D816V VAF, and 20 (13%) reached a KIT D816V VAF below 0.022%, the LOD. No new on-treatment KIT mutations were detected by NGS in any patients. At baseline, 25/245 (10%) patients had additional non-KIT Tier-1 (i.e., known pathogenic) mutations. Tier-1 mutations in non-KIT genes occurring in more than 1 patient included DNMT3A (n=14, median VAF 9.4%), TET2 (n=3, median VAF 8.5%), CBL (n=2), and TP53 (n=2). Following 24 weeks (n=241) of avapritinib treatment, the fraction of patients with detectable non-KIT Tier-1 mutations in the PB had decreased to 6% (n=15) and following ≥48 weeks (n=234) of avapritinib treatment, this fraction had decreased further to 4% (n=10). After ≥48 weeks of avapritinib therapy, no patient had the emergence of a new non-KIT Tier-1 mutation that was not detected in baseline testing. Furthermore, comparing paired samples taken both at baseline and after ≥48 weeks of avapritinib therapy, 57% (n=8/14) of patients had a reduction in the VAF of the non-KITTier-1 mutations, including 4 patients with undetectable clonal frequencies for such mutations. The DNMT3A gene was most frequently reduced or eliminated.

Conclusion: Longer-term avapritinib therapy is associated with favorable clonal dynamics in patients with ISM. After nearly a year of therapy, there was no emergence of drug-resistance mutations in KIT, nor the appearance of additional pathogenic mutations in other genes commonly implicated in hematologic malignancies. These data suggest that avapritinib treatment in ISM does not promote the emergence of clonal hematopoiesis and, in some cases, is associated with regression of abnormal clones. Understanding whether treatment can modify rates of progression to SM with associated hematological neoplasms would require larger prospective studies and longer follow-up.

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2025
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