Mutations Associated with Progression in Follicular Lymphoma Predict Inferior Outcomes at Diagnosis (Alliance A151303).

Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, while others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from CALGB/Alliance trials 50402/50701/50803 or real-world cohorts from WUSM/CC/UM). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than t-FL, yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than dx FL, including six significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a Mutations Associated with Progression (MAP) signature as >=2 mutations in these seven genes (six rel/ref/t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a seven-gene set offering insight into FL progression risk potentially more generalizable than the m7-FLIPI, which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in these high-risk patients.