Longitudinal Molecular Characterization of a Rare TPM3::PDGFRB ‐Rearranged Myeloid/Lymphoid Neoplasm With Late CNL ‐Like Neutrophilic Evolution

OBJECTIVES: Myeloid/lymphoid neoplasms with tyrosine kinase fusions are rare but important because many are highly sensitive to targeted therapy. PDGFRB rearrangements are well-established drivers, whereas TPM3 is an exceptionally rare fusion partner. METHODS: We performed longitudinal analysis of an elderly patient with hypereosinophilia, integrating morphology, cytogenetics, PDGFRB break-apart FISH, whole-transcriptome RNA sequencing, optical genome mapping, targeted myeloid DNA sequencing and exploratory fusion-specific RT-qPCR. RESULTS: A balanced t(1;5)(q21;q33) with PDGFRB rearrangement in 70% of nuclei was identified at diagnosis. RNA sequencing detected an in-frame TPM3 exon 8-PDGFRB exon 11 fusion, and optical genome mapping confirmed the balanced rearrangement. Low-dose imatinib induced durable haematologic and cytogenetic remission of the fusion-driven eosinophilic component. Serial DNA sequencing identified diagnostic ASXL1, EZH2 and low-level SRSF2 abnormalities that persisted during remission, followed by acquisition or expansion of SETBP1, CSF3R, ETNK1 and a distinct SRSF2 variant during late neutrophilic progression, without re-emergence of the PDGFRB rearrangement. CONCLUSIONS: TPM3::PDGFRB is a rare but actionable PDGFRB fusion. Durable suppression of the fusion-positive eosinophilic component was followed by a late CNL-like neutrophilic phase. The clonal relationship between these phases remains unresolved. Integrated longitudinal fusion testing and myeloid mutational profiling are therefore essential to characterize disease complexity.