Longitudinal Molecular Characterization of a Rare
TPM3::PDGFRB
‐Rearranged Myeloid/Lymphoid Neoplasm With Late
CNL
Frédéric Lambert, Benjamin Koopmansch, Rafael Fernandez Carazo, Elisa Dardenne, Aurore Keutgens, Gaëtan Vanstraelen, Patrick Collins, Catherine Menten, Gaëlle Vertenoeil ABSTRACT
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.