Background: Systemic mastocytosis (SM) is a hematologic neoplasm that includes advanced and non-advanced subtypes. The latter includes bone marrow mastocytosis, indolent SM (ISM), and smoldering SM (SSM). Non-advanced SM subtypes are distinguished by the lack of C-findings (end organ damage), with the number of concurrent B-findings (burden of disease) further informing subtype diagnosis. SSM is defined by the presence of ≥2 B-findings, including high mast cell (MC) burden, organomegaly, or histopathologic evidence of myeloproliferation and/or myelodysplasia, and not meeting criteria for an associated hematologic neoplasm. The definition of B-findings has evolved with the advance of disease understanding and technology to better classify patients across the spectrum of non-advanced SM subtypes. Droplet digital PCR (ddPCR; to sensitively detect and quantify KIT D816V variant allele frequency [VAF]), and next generation sequencing (NGS; to detect occult co-occurring mutations), are recent advances that can be used to assess disease burden in SM.

In 2022, the World Health Organization (WHO) updated B-finding definitions so that bone marrow (BM) MCs ≥30%, and/or serum tryptase ≥200 ng/mL, and/or KIT D816V VAF ≥10% are classified as a high MC burden B-finding. The WHO 2016 criteria outlined that both BM MC and serum tryptase had to be concurrently elevated and did not include KIT D816V VAF. The PIONEER (NCT03731260) study, which led to the approval of avapritinib for the treatment of ISM, includes one of the largest, most well-characterized populations of patients with ISM, per WHO 2016 criteria. This enabled the use of data from PIONEER to explore these evolving diagnostic criteria and their impact on SM subtype diagnosis.

Methods: Serum tryptase level, BM biopsy, and peripheral blood samples for the assessment of KIT D816V VAF and other somatic mutations were collected at the time of study enrollment. NGS testing for mutations in 54 genes was performed using the Illumina TruSight Myeloid Sequencing Panel. Investigators measured liver and spleen size by palpation at enrollment. Histopathology was assessed via central review by expert hematopathologists. A retrospective analysis assessed B-finding distribution at baseline using WHO 2016 and WHO 2022 criteria.

Results: A total of 251 patients with ISM with moderate-to-severe symptoms enrolled in PIONEER. Under WHO 2016 criteria, 4/251 patients (2%) met the elevated MC burden B-finding (BM MC >30% and serum tryptase >200 ng/mL); none had ≥2 B-findings (i.e., no SSM). Per WHO 2022 criteria, 53 patients (21%) met the revised high MC burden B-finding (BM MC ≥30% and/or serum tryptase ≥200 ng/mL and/or KIT D816V VAF ≥10%) and 8 patients (3%) had ≥2 B-findings (i.e., SSM). The significant increase in patients between WHO 2016 and WHO 2022 criteria was in part due to the inclusion of KIT D816V VAF ≥10%. A total of 26 patients had KIT D816V VAF ≥10%, including 17 patients who did not have concurrent BM MCs ≥30% and/or serum tryptase ≥200 ng/mL. Lowering the KIT D816V VAF threshold to 6% (previously shown to be a specific but insensitive marker of multilineage involvement of the KIT D816V mutation), would capture an additional 9 patients with high MC burden. We also explored the interaction of NGS results with other B-findings. Among patients with available NGS data, 25/245 (10%) harbored non-KIT pathogenic mutations in genes associated with hematologic malignancies (e.g., DNMT3A, TET2, CBL, TP53). Of these 25 patients, 1 patient met the WHO 2022 criteria for SSM and 7 patients exhibited a B-finding in addition to the Tier-1 mutation.

Conclusions: The expansion of the B-finding definitions from WHO 2016 to WHO 2022 led to considerably more patients meeting the high MC burden B-finding (4 vs 53 patients) and led to an increase in the number of patients with SSM enrolled on PIONEER from 0 to 8. These findings highlight the heterogeneity of ISM.KIT D816V VAF is a disease burden finding distinct from serum tryptase and BM MC. The specific KIT D816V VAF threshold that best correlates with prognostic risk has yet to be determined and needs to be further explored. Patients with ISM and concurrent non-KIT mutations represent a unique subset, largely uncaptured by current B-finding definitions. While the population enrolled on PIONEER included patients with ISM with moderate-to-severe symptoms, novel insights from clinical trials can help to improve future SM classification and management.

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2025
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