Purpose: The selective tyrosine kinase inhibitor avapritinib has been shown to improve skin lesions in pts with ISM (Hartmann K et al. EACCI 2020. Abstract 1832). We assessed numbers and immunophenotypic changes of MCs in bone marrow (BM) and skin biopsies from lesional tissue (LT) and non-lesional tissue (NLT) in 39 pts with ISM from Part 1 of the placebo-controlled PIONEER (NCT03731260) study. Methods: BM biopsies and aspirates were obtained at Screening; skin biopsies from LT and NLT were obtained at Screening and end of Week 12 (W12). Immunohistochemistry was performed on formalin-fixed sections using the Ventana Benchmark assay with CD117, tryptase, CD25, CD30, and CD34 antibodies. Samples were centrally reviewed by three pathologists. Statistical significance of MC numbers and immunophenotypic changes were assessed. Data cut-off was December 4, 2020. Results: Screening BM biopsies had median 10% (range, 1-60%) MCs, of which 90% (10-100%) were spindled. BM aspirates had median 1% (0-10%) MCs, of which 5% (2-6%) were immature. Median number of MCs/mm2 was 355 (53-4300) in LT and 90 (10-540) in NLT. At W12, avapritinib reduced median number of MCs/mm2 in LT (143 [33-837]) but not NLT (102 [32-207]). BM biopsies had higher median rates of CD25+ and CD30+ MCs (90% CD25+/50% CD30+) compared with skin LT (2% CD25+/10% CD30+) and NLT (1% CD25+/1% CD30+) (Table). Avapritinib produced significant reductions in the proportion of CD30+ MCs in LT at W12 versus placebo (P=0.0053) and non-significant reductions in CD30+ MCs in NLT (P=0.0988).

Conclusions: CD25+ and CD30+ MCs were observed in both LT and NLT skin biopsies; however, at markedly lower levels than seen in BM. Treatment with avapritinib decreased the total number of MCs as well as the number of CD30+ and CD25+ MC in both LT and NLT with statistically significant decreases in the CD30+ MC fraction in LT. This is the first study to examine changes in MCs in LT and NLT or ISM during precision therapy of ISM.

Table. Immunophenotypic changes of MCs in BM and skin biopsies at screening and W12

MC PhenotypeBone MarrowSkin Lesional TissueSkin Non-Lesional Tissue
AvapritinibPlaceboAvapritinibPlacebo
Screening (n=39)Screening (n=25)W12 (n=17)Screening (n=8)W12 (n=7)Screening (n=25)W12 (n=21)Screening (n=8)W12 (n=7)
CD25+, median % (range) 90 (0-100) 2 (1-40) 2 (1-10) 3 (1-50) 5 (2-5) 1 (1-5) 2 (1-10) 2 (1-5) 5 (2-5) 
CD30+, median % (range) 50 (0-100) 10 (1-100) 1 (1-5) 13 (1-80) 5 (1-30) 1 (1-20) 1 (1-2) 2 (1-30) 1 (1-10) 
MC PhenotypeBone MarrowSkin Lesional TissueSkin Non-Lesional Tissue
AvapritinibPlaceboAvapritinibPlacebo
Screening (n=39)Screening (n=25)W12 (n=17)Screening (n=8)W12 (n=7)Screening (n=25)W12 (n=21)Screening (n=8)W12 (n=7)
CD25+, median % (range) 90 (0-100) 2 (1-40) 2 (1-10) 3 (1-50) 5 (2-5) 1 (1-5) 2 (1-10) 2 (1-5) 5 (2-5) 
CD30+, median % (range) 50 (0-100) 10 (1-100) 1 (1-5) 13 (1-80) 5 (1-30) 1 (1-20) 1 (1-2) 2 (1-30) 1 (1-10) 

Abbreviations: BM, bone marrow; MC, mast cell; W12, Week 12.

Citation Format: Tracy George, Sigurd Broesby-Olsen, David Wada, Scott Florell, Karin Hartman, Frank Siebenhaar, Cem Akin, Kate Newberry, Hongliang Shi, Maria Roche, Marcus Maurer, Hanneke Oude Elberink. Changes in mast cell (MC) numbers and phenotype in patients (pts) with indolent systemic mastocytosis (ISM) treated with avapritinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT168.