Large clones of Clonal Hematopoiesis affect outcome in Mantle Cell Lymphoma: Results from The FIL MCL0208 Clinical Trial

• Young untreated MCL patients show 13% prevalence of myeloid clonal hematopoiesis at baseline

• In contrast to small clones, large M-CH clones (VAF ≥ 10%) are associated with higher MCL progression and worse PFS and OS.

Although recent evidence suggests that myeloid clonal hematopoiesis (M-CH) may influence lymphoma clinical outcome, its impact in mantle cell lymphoma (MCL) remains unclear. Here, we report a comprehensive NGS-based analysis of the M-CH mutational landscape at baseline and follow-up in patients enrolled in the Fondazione Italiana Linfomi (FIL) MCL0208 phase 3 trial (NCT 02354313), evaluating lenalidomide maintenance versus observation after chemoimmunotherapy and autologous stem cell transplantation (ASCT) in untreated young MCL patients. Overall, 254/300 (85%) enrolled patients (median age 57 years [32-66]) had a baseline sample available for CH analysis. Using stringent criteria, at least one mutation involving M-CH candidate genes was described in 34 patients (13%), with DNMT3A being the most frequently mutated gene (54%). After a median follow-up of 7 years, the presence of large CH clones (VAF ≥ 10%) predicted worse PFS (HR 2.93 [1.36-6.31], p=0.006) and OS (HR 3.02 [1.21-7.55], p=0.018) compared to CH- patients. Importantly, the competing risks analysis demonstrates that the worse clinical outcome associated with M-CH large clones is linked to MCL progression (P<0.05). Moreover, large M-CH clones showed longer time to hematologic recovery after ASCT compared to the remaining cohort (p=0.026). In conclusion, we showed for the first time that large CH clones might associate with unfavorable clinical impact in MCL patients.