Histopathologic and Clinical Characteristics of Cutaneous Toxicities of Tyrosine Kinase Inhibitors: Insights Into Pathologic Mechanisms From a Retrospective Cohort.

Background: Dermatologic adverse events (dAEs) are prevalent with BCR-ABL tyrosine kinase inhibitors (TKIs), affecting quality of life and treatment adherence. Despite their prevalence, underlying mechanisms of toxicity remain unclear. We sought to characterize dAEs across TKI generations to elucidate mechanisms driving toxicities.

Methods: Retrospective cohort study of patients receiving imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib at Memorial Sloan Kettering Cancer Center between 2001 and 2023 with dermatologic biopsy for TKI-related dAEs. Clinical and histopathologic characteristics were analyzed. Fisher exact test, with Freeman-Halton extension, was used to determine statistically significant differences.

Results: Among 28 patients with 32 unique dAEs, imatinib was implicated in 32.1% of patients, second-generation TKIs in 57.1%, and ponatinib in 10.7%. Imatinib-induced dAEs exhibited significantly higher rates of papular/plaque morphology (P = 0.02) with acanthosis (P = 0.001) and eosinophilic infiltrates (P = 0.02). Second-generation TKIs frequently caused folliculocentric eruptions with adnexal involvement. Ponatinib-related dAEs demonstrated significantly higher rates of ichthyosiform (P = 0.002) and pityriasiform (P = 0.02) morphologies with hyperkeratosis and fibrosis. No biopsy-confirmed asciminib dAEs were available.

Conclusions: dAE pathogenesis varies across TKI generations, suggesting distinct patterns of inflammation and keratinocyte dysregulation. Imatinib-related dAEs demonstrated epidermal hyperplasia and eosinophilic inflammation, suggesting immune-mediated hypersensitivity as an important mechanism of toxicity. Second-generation TKI dAEs demonstrated prominent adnexal and perivascular involvement, possibly driven by off-target inhibition and proinflammatory mechanisms. Ponatinib dAEs reflected chronic epidermal alterations, possibly driven by off-target vascular endothelial growth factor receptor, fibroblast growth factor receptor, and Src-family kinase inhibition. Limited sample size, particularly for third-generation TKIs, limits generalizability. Understanding these differences may improve management strategies, optimizing patient quality of life and treatment continuation.