P003 | CLONAL HEMATOPOIESIS IN FOLLICULAR LYMPHOMA: ANALYSIS OF THE PHASE III FIL FOLL12 TRIAL

INTRODUCTION: Clonal Hematopoiesis (CH) is an age-related phenomenon, characterized by the accumulation of somatic mutations involved in myeloid malignancies in individuals without myeloid tumors. The clinical interplay between CH and follicular lymphoma (FL), has not been fully elucidated yet. METHODS: The study analyzed 212 FL patients treated with R-CHOP or BR in the phase III FIL FOLL12 trial. At diagnosis, genomic DNA from whole peripheral blood was assessed for CH using CAPP-Seq-based NGS. The gene panel included 28 genes frequently involved in CH and a VAF of 1% was set for variant calling. RESULTS: CH mutations were identified in 75 cases (35.4%) with DNMT3A (17.5%), TET2 (10.8%), TP53 and CUX1 (2.8%) being the most common affected genes. CH⁺ patients had a significantly higher median age of 66 years compared to 57 for CH^- patients (P<0.001). CH⁺ patients showed superimposable PFS compared to CH^- patients with a 72-month PFS of 66.4% compared to 63.3%, respectively (P=0.576) (Fig.1A). CH⁺ and CH^- patients also displayed a similar OS (Fig.1B). Precisely, CH⁺ patients showed a 72-month OS of 91.3% compared to 93.9% in CH^- patients (P=0.532). These results suggest that CH does not affect PFS or OS in FL patients after front-line therapy. CH was then correlated to therapy-related hematological toxicities, including anemia, neutropenia, and thrombocytopenia of any grade or grade ≥3. TET2 mutations sorted out as a molecular predictor of hematological toxicities. Precisely, 78.3% (N=18) of TET2 mutated patients showed presence of hematological toxicities of any grade compared to 52.4% (N=99) of TET2 wild type cases (P=0.018). Similar results were obtained when restricting the analysis to only grade ≥3 hematological toxicities (Fig.1C). Specifically, TET2 mutated patients significantly associated with grade >3 neutropenia, that developed in 60.9% (N=14) of TET2 mutated patients compared to 37.6% (N=71) of TET2 wild type patients (P=0.031) (Fig.1D). CONCLUSIONS: CH does not associate with poor outcomes in FL patients when treated in 1^st line with R-CHOP or BR, which remain the standard of care regimens. However, CH TET2 mutations associate with a higher frequency and a higher grade of hematological toxicity in FL patients treated with chemoimmunotherapy. In this respect, CH may be used as a precision medicine biomarker to identify a subset of FL patients who could benefit from chemo-free approaches in order to spare unnecessary therapy-related toxicities.