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PATHFINDER Study Reveals Potential for Avapritinib to Modify Progression of Advanced Systemic Mastocytosis

Conference Correspondent

Systemic mastocytosis (SM) is characterized by hyperactivation and accumulation of mast cells in multiple organs. Mutation in KIT D816V accounts for >95% of total cases of advanced systemic mastocytosis (AdvSM). Avapritinib, a KIT D816V inhibitor, has been evaluated in phase 1 (EXPLORER) and phase 2 (PATHFINDER) clinical trials. Data from these studies led to the recent FDA approval of avapritinib to treat AdvSM. EXPLORER results demonstrated avapritinib markedly reduced the bone marrow mast-cell burden in patients with AdvSM. In this report, researchers presented findings from PATHFINDER on the effect of avapritinib on mast-cell burden as well as morphology, bone marrow immunohistochemistry, cellularity and fibrosis, and changes in hematologic parameters.

The PATHFINDER trial evaluated the effects of a 200-mg daily dose of avapritinib in 107 patients aged ≥18 years with AdvSM (66.4% SM with associated hematologic neoplasm, 19.6% aggressive SM, and 14% mast-cell leukemia). At screening week 8 and week 24, investigators collected peripheral blood smears and bone marrow aspirates and performed bone marrow biopsies to observe changes in mast-cell burden and morphology, bone marrow, and blood cell counts. Mast cells present in the bone marrow decreased by ≥50% in 83.8% (88/105) of patients. Of note, for 60% of patients (63/105), avapritinib treatment resulted in elimination of bone marrow mast-cell aggregates. By weeks 8 and 24, bone marrow biopsies also showed an overall average decrease in mast-cell burden (66.1% and 55.3%, respectively) as well as the proportion of CD25+ and CD30+ mast cells. Similarly, an 11% reduction in mast-cell burden was also observed at weeks 8 and 24 compared with baseline. In addition, fewer mast cells with abnormal morphological changes were observed in bone marrow aspirates. In 7 patients with circulating mast cells at baseline, avapritinib treatment reduced circulating mast cells to undetectable levels by week 8.

Bone marrow fibrosis was observed in 99% of 104 evaluable biopsy samples. Compared with initial screening, biopsy results also showed reductions in cellularity (mean of 85.4% at baseline to 66.1% at week 8) and fibrosis (99%-92.6%) at week 8; this effect was further reduced at week 24 evaluation (82.8%). An overall response rate of 75% was achieved in patients treated with avapritinib. Reductions in mean eosinophil, white blood cell, neutrophil, and monocyte counts were observed in peripheral blood samples but there was no significant change in hemoglobin.

Results from PATHFINDER provide further evidence supporting avapritinib treatment in patients with AdvSM. Responses to avapritinib were robust within 8 weeks of treatment and were further reduced by week 24 in observed parameters, including reduced overall mast-cell burden, restoration of normal cell morphology immune marker expression, and reduced blood cell counts in peripheral blood. Taken together, these data indicate avapritinib therapy can alter disease progression and improve clinical outcomes.

George TI, Karner KH, Moser KA, et al. Efficacy of avapritinib in patients with advanced systemic mastocytosis: hematologic and bone marrow responses from the phase 2 open-label, single-arm, Pathfinder study. 2021 American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 2565.

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