Clonal hematopoiesis dynamics influences long‐term outcomes of follicular lymphoma: Results from FIL FOLL12 trial

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Abstract Whether clonal hematopoiesis (CH) in follicular lymphoma (FL) patients affects clinical outcome or is merely a bystander phenomenon is unclear. We leveraged the Phase III Fondazione Italiana Linfomi FOLL12 trial, which treated patients with advanced‐stage FL with R‐CHOP or R‐Bendamustine, to evaluate the role of myeloid CH at baseline and after chemoimmunotherapy (CIT). A total of 528 serial blood samples from 242 FL were analyzed by CAPP‐Seq. At baseline, CH occurred in 35.5% patients with DNMT3A ( N = 41, 16.9%) and TET2 ( N = 29, 12.0%) being the most frequently mutated genes. After a median follow‐up of 8.2 years, CH at baseline did not impact progression‐free survival (PFS), overall survival (OS), or risk of transformation (P = 0.660, P = 0.230, and P = 0.584, respectively), but instead associated with therapy‐related hematological toxicities driven by TET2 mutations. CH dynamics after the genotoxic pressure imposed by CIT was evaluated in 211 patients provided with sequential samples. CIT significantly expanded both prevalence and size of CH, with clones affected by DNA damage response (DDR) gene mutations exhibiting the highest fitness. Distinct selective pressures were observed between R‐CHOP and R‐Bendamustine, with the latter creating a tighter bottleneck that facilitates the emergence of fitter CH clones preferentially carrying TP53 mutations. Patients acquiring fit DDR clones ( N = 37) had inferior long‐term outcomes, including independent increased risk of second malignancies (hazard ratio [HR] 2.63, P = 0.035) that developed in 28 patients, and shorter OS (HR 3.28, P = 0.008). CH emerges as a novel and potentially valuable biomarker in FL, capable of predicting long‐term toxicities that are key endpoints in indolent lymphoid malignancies characterized by long‐lasting survival.

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