T-follicular helper cell lymphomas (TFHL) are frequently associated with epigenetic mutations and clonal hematopoiesis (CH), but the clinical and prognostic implications of CH in TFHL remains unclear. We performed next-generation sequencing on paired peripheral blood (PB) and formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 30 patients diagnosed with TFHL. CH was defined by detection of CH-associated mutations in PB at variant allele frequency (VAF) ≥ 2%. Patients were stratified into CH-positive, CH-suspected, or CH-negative based on genotyping and bone marrow involvement. CH-associated mutations were detected in PB in 12 of 30 patients (40.0%) and were suspected in 4 additional cases (13.3%), with no cases progressed to overt myeloid neoplasms. TET2 and DNMT3A were the most frequently shared mutations between tumor and PB, suggesting a common hematopoietic stem cell (HSC) origin. In contrast, IDH2 and RHOA mutations were confined to tumor samples, representing tumor-specific second-hit lesions. CH-positive patients were significantly older, exhibited poorer performance status (ECOG ≥2: 50.0% vs. 0.0%, P = 0.004), elevated systemic inflammation (hs-CRP: 66.9 vs. 20.3 mg/L, P=0.010), and inferior treatment response (CR rate: 9.1% vs. 50.0%, P=0.042). CH positivity was also associated with inferior progression-free survival (HR=2.455, 95% CI: 1.020–5.910, P=0.044). In conclusion, CH is common in TFHL and is associated with elevated systemic inflammation, poor performance status, worse treatment response, and inferior progression-free survival. These results further support a stepwise model of lymphomagenesis, where CH-related TET2 and/or DNMT3A mutations in HSCs represent early events, followed by acquisition of tumor-specific drivers mutations such as RHOA and IDH2.

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2025
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