Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Methods: Part 1 of PIONEER included 39 patients (3 cohorts with 10 patients at 25, 50 and 100 mg of avapritinib, and a placebo cohort of 9 patients) with a confirmed diagnosis of ISM based on World Health Organization criteria and moderate-to-severe symptoms based on Total Symptom Score as measured on the ISM-System Assessment Form (ISM-SAF). Samples of PB were collected at screening for all enrolled patients in part 1 and were evaluated by local quantitative and qualitative KIT testing, central ddPCR assay for detection of KIT D816V, and central NGS (TruSight™ Myeloid Panel) for KIT D816V and other co-mutations (central assays performed by MolecularMD, Portland, OR). Results were expressed as the percentage of patient PB samples testing positive for KIT D816V mutation (all genomic assays) and the log percent of VAF as measured by both central assay methods. Correlations of KIT D816V VAF to objective measure of MC burden, including serum tryptase levels and BM MC numbers, were performed. KIT D816V VAF was also evaluated serially in each patient over the treatment period.
Results: The central ddPCR assay method detected the KIT D816V mutation in 37/39 (95%) of PB samples compared with 11/39 (28%) assayed by NGS and 30/39 (80%) of PB samples assayed locally (Table). ddPCR also demonstrated ~30-fold greater sensitivity over NGS for measuring VAF: median percent VAF (range) by ddPCR was 0.36 (0.02–30) and by NGS was 11 (1.9–31) (Figure). The lower limit of detection of VAF by ddPCR on PB samples was 95-fold lower than that of NGS (0.02% and 1.9%, respectively). In addition, ddPCR provided greater diagnostic sensitivity for ISM compared with serum tryptase >20 ng/mL (30/39, 77%) and presence of BM MC aggregates (35/39, 90%).
Conclusions: The high-sensitivity ddPCR assay method detected the KIT D816V mutation in 95% of PB samples from patients with previously confirmed ISM, which provided greater sensitivity for detection of KIT D816V mutation than either NGS or local assessments, greater sensitivity over NGS for KIT D816V VAF in PB samples, and higher diagnostic sensitivity than clinical assessments of serum tryptase and BM MC aggregates. These results have implications for assay sensitivity in the diagnosis of SM and suggest that higher sensitivity testing for KIT D816V mutation using a minimally invasive PB ddPCR assay could be used as a screening tool to facilitate identification of ISM patients, including those with variable disease characteristics or low MC burden.
Disclosures: George: Blueprint Medicines Corporation: Consultancy, Other: I have received no funding for this research. ARUP Laboratories, owned by the University of Utah, has received funding; Celgene: Consultancy; Incyte: Consultancy; Deciphera: Other: consultancy, but has received no financial compensation for the past 12 months; Allakos: Consultancy. Hoehn: Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Lin: Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Miller: Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Akin: Novartis: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding.
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