Prognostic value of the end of induction PET in patients with follicular lymphoma: results from the analysis of FOLL 12 trial

Aim: To assess the prognostic value of the PET metabolic response using the Deauville Score at the end of induction (EoI) therapy. Methods: FOLL12 trial (NCT02063685) is a multicenter, phase III, randomized study with the primary objective to evaluate whether a FDG-PET (PET) and MRD (molecular residual disease) response-based maintenance therapy (experimental arm) is more effective in terms of Progression-Free Survival (PFS) than a standard maintenance therapy with Rituximab (standard arm) in patients with follicular lymphoma. Adult patients with untreated grade 1–3a FL and stage II-IV were randomized to receive standard immunochemotherapy followed by rituximab maintenance versus standard immunochemotherapy followed by a response adapted post-induction management (i.e. non-maintenance for patients in CMR and with MRD negative, short rituximab therapy for CMR (complete metabolic response) and MRD +ve cases and radioimmunotherapy followed by rituximab maintenance for non-CMR patients). EoI-PET was mandatory. All PET scans were centralized on WIDEN® platform and classified according to Deauville score (DS) in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. Main secondary endpoint was Overall Survival (OS) Results: Overall, 729 follicular lymphoma patients, 52% women, 89% stage III-IV disease and 40% with a high-risk FLIPI-2 score, were included in the analysis. DS at the EoI-PET resulted 1,2,3,4, and 5 in 361(49.5%), 168(23.1%), 112(15.4%), 49(6.7%) and 39(5.3%) patients, respectively. EoI-PET resulted positive in 88/729 (12%). Among the reviewers, the overall agreement (OA) on PET pos/neg result was 0.92, while agreement on positive and negative cases were 0.77 and 0.94, respectively. In the whole population of 729 patients, 5 yrs PFS (95% CI) for DS1-3 and DS4-5 was 69%(65–73) and 35%(25–46) with HR3.32(2.45–4.50), p < 0.001, respectively. The 5 yrs OS (95% CI) in DS1-3 and DS4-5 was 94%(92–96) and 81%(71–88), HR4.72(2.69–8.32), p < 0.001. The prognostic role of CMR was confirmed both in the standard and in the experimental arm of the study. In the whole population, the 5 yrs PFS (95% CI) in DS1-2, DS 3 ad DS4-5 was 74% (69–78), 55% (44–65; HR1.90 (1.36–2.66) p < 0.001) and 37%(26–48; HR 4.01 (2.90–5.54) p < 0.001); DS3 patients had an intermediate 5 yrs PFS rates between those of DS1-2 and DS4-5 patients. OS in DS3 patients had similar values to those with DS1-2. Applying a different definition of CMR (i.e., DS1-2 only) the rate of positive EoI-PET rose to 27%. Conclusion: In FOLL12 trial, EoI-PET according DS criteria was a reliable tool to stratify PFS and OS in advanced follicular lymphoma patients treated with immunochemotherapy; in addition, these data showed DS3 patients as a new category with an intermediate prognosis in terms of PFS. Keywords: Diagnostic and Prognostic Biomarkers, PET-CT No conflicts of interests pertinent to the abstract.