Background:

Advanced systemic mastocytosis (AdvSM), a hematologic malignancy driven by activating KIT mutations, is defined by organ damage (“C-findings”) and includes aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Current first-line treatments target the KIT driver mutation and include the multi-kinase inhibitor midostaurin and the selective KIT D816V inhibitor avapritinib. This study aims to compare real-world survival and safety outcomes between these two first-line regimens.

Methods:

A retrospective analysis was conducted using the de-identified TriNetX US electronic health record network. We identified patients aged ≥18 years with a new diagnosis of AdvSM using specific ICD-10 codes for ASM, MCL, and SM-AHN. Two mutually exclusive, treatment-naive cohorts were created: patients initiated on avapritinib and those initiated on midostaurin. The cohorts were 1:1 propensity score matched (PSM) for age, sex, race, ethnicity, and a comprehensive panel of comorbidities. The primary endpoint was Overall Survival (OS), assessed using Kaplan-Meier analysis. Secondary outcomes included mortality risk and incidence of adverse events.

Results:

We identified 174 eligible AdvSM patients. After 1:1 PSM, 76 patients remained in the avapritinib cohort and 76 in the midostaurin cohort. Baseline characteristics were well-balanced post-matching. The mean age was 64.0 and 63.8 years, respectively, and cohorts were predominantly male (56.6% vs. 56.6%) and White (77.6% vs. 76.3%). The analysis demonstrated a significant OS benefit for avapritinib. At 24 months, the Kaplan-Meier estimated survival probability was 89.8% for the avapritinib cohort versus 53.8% for the midostaurin cohort (log-rank p<0.001). The hazard ratio (HR) for mortality strongly favored avapritinib (HR 0.19, 95% CI 0.08–0.46). Avapritinib was also associated with a significantly lower mortality risk (Risk Difference: –25.4%, p=0.001; Odds Ratio: 0.26, 95% CI 0.11–0.60). No significant difference in osteoporosis or fracture risk was observed. The incidence of key avapritinib-associated adverse events was low; no cases of intracranial hemorrhage were recorded, and cognitive effects were rare.

Conclusion:

In this large, real-world analysis of first-line therapy for AdvSM, avapritinib was associated with a statistically significant and clinically meaningful improvement in overall survival compared to midostaurin. These findings, coupled with a favorable observed safety profile, support the preferential use of avapritinib in the first-line treatment of Advanced Systemic Mastocytosis.

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2025
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