Clonal haematopoiesis in T-follicular helper cell lymphoma: A prognostic biomarker and early event in lymphoma evolution

T-follicular helper cell lymphomas (TFHLs) are frequently associated with epigenetic mutations and clonal haematopoiesis (CH), but the clinical and prognostic implications of CH in TFHL remains unclear. We performed next-generation sequencing on paired peripheral blood (PB) and tumour tissue samples from 30 patients with TFHL. CH was defined by the detection of CH-associated mutations in PB at variant allele frequency ≥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 four additional cases (13.3%), with no cases progressed to overt myeloid neoplasms. Ten-eleven translocation 2 and DNA methyltransferase 3A were the most frequently shared mutations between tumour and PB. CH-positive patients were significantly older, exhibited poorer performance status (Eastern Cooperative Oncology Group [ECOG] ≥2: 50.0% vs. 0.0%, p = 0.004), elevated systemic inflammation (high-sensitivity C-reactive protein [hs-CRP]: 66.9 vs. 20.3 mg/L, p = 0.010) and inferior treatment response (complete response [CR] rate: 9.1% vs. 50.0%, p = 0.042). In multivariate analysis adjusting for age and ECOG performance status, CH positivity remained independently associated with inferior progression-free survival (PFS) (hazard ratio [HR] = 4.41, 95% confidence interval [CI]: 1.46-13.35, p = 0.009), even after adjustment for age and ECOG performance status. In conclusions, CH is common in TFHL which represents early events in lymphomagenesis and is associated with elevated systemic inflammation, poor performance status, worse treatment response and inferior PFS.