Background. The FOLL12 study demonstrated that in High tumor burden patients with Follicular lymphoma (FL) treated with immunochemotherapy (ICT), standard rituximab maintenance (RM) was associated with improved Progression Free Survival (PFS) compared with a response-adapted post-induction approachbased on metabolic response and molecular assessment of minimal residual disease (MRD). We here present updated results of study endpoints after a median follow up of 7.9 years.

Methods. The FOLL12 study enrolled adult patients with gr1-3a FL, advanced stage and high tumor burden. Eligible patients were randomly assigned to receive ICT with either R-CHOP or R-Bendamustine followed by standard RM or a response-adapted post-induction approachbased on metabolic response and molecular assessment of minimal residual disease (MRD).End of Induction (EOI) metabolic response was centrally defined applying the 5-point Deauville scale (DS) that defined Complete metabolic response (CMR) in case of DS 1-3. MRD was defined according to nested PCR assessment of IGH::BCL2 rearrangement on bone marrow and peripheral blood and was evaluated only for patients with a molecular marker (MM) at baseline assessment. Post induction therapy in the experimental arm consisted of: CMR and MRD- patients, observation; CMR and MRD+ (EOI or Follow up) 4 weekly rituximab until MRD- for up to 3 courses; no CMR, one dose of ibritumomab tiuxetan followed by standard RM. The primary study endpoint was Progression Free Survival (PFS).

Results. A total of 807 patients were randomized and 786 were eligible for this updated analysis. After a median follow-up of 7.9 years (range 0.1 to 12.3 years), median PFS was not achieved and 5 and 10-year PFS rates were 67% (95%IC 63-70%) and 54% (49-58). Also with this updated follow up the standard RM arm was associated with improved PFS rates vs the response adapted arm (Exp. vs STD HR 1.54, 95%CI 1.23-1.93). After first progression 270 patients received a second line therapy mainly represented by an alternative ICT combination. PFS and OS rates after first relapse were 41% and 78% at 5 years respectively without difference comparing the main therapeutic options. Overall, after the induction 85 second malignancies were reported, including 37 hematologic malignancies and 48 solid cancers out of 744 patients. The cumulative risk of 2nd malignancy at 5 year was 13.2%, with a trend for higher risk for patients treated with RB vs R-CHOP (HR adjusted for age, sex, FLIPI2, study arm 1.48 (CI95% 0.96– 2.28). The 5-year cumulative risk of tFL from start of induction was 4.2%. with significant higher risk associated with the use of RB vs R-CHOP (HR adjusted for age, sex, FLIPI2 and Arm 2.26, CI95% 1.10 – 4.63). Overall 15 late infections were reported starting from the end of induction therapy, corresponding to a rate of 1.4% and 2.9% in RCHOP and RB, respectively (logrank p=0.022). Out of 101 deaths, 33 were due to progressive disease, 13 infections, 12 second malignancy 28 for other non lymphoma related causes and 15 for unknown reasons, resulting in 5 and 10-year Overall Survival (OS) rates of 92% (90-94) and 82% (78-86), respectively. Comparing study arms no differences were observed in terms of OS rates (HR 1.20, 95%CI 0.81–1.77).

Conclusions.

This long term updated analysis of the FOLL12 study demonstrated that high tumor burden FL patients initially treated with ICT are offered excellent outcomes with more than half of the patients who don't relapse after first line therapy and with very high survival rates. Also with the longer follow up standard RM was associated with improved PFS vs the response adapted approach but still no difference in term of OS was observed. While similar excellent results are achieved in terms of long term outcomes the choice of initial ICT may result in different risks in terms of late events mainly represented by second malignancies, tFL and infections.

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2025
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