Low Suvmax Measured on Baseline FDG-PET/CT and Elevated β2 Microglobulin Are Negative Predictors of Outcome in High Tumor Burden Follicular Lymphoma Treated By Immunochemotherapy: A Pooled Analysis of Three Prospective Studies
Authors: Cottereau Anne Ségolène , Versari Annibale , Chartier Loïc , Dupuis Jehan , Tarantino Vittoria , Casasnovas Rene-Olivier , Franceschetto Antonella , Itti Emmanuel , Tilly Hervé , Haioun Corinne , Federico Massimo , Berriolo Alina , Salles Gilles Andre , Luminari Stefano , Meignan Michel , Trotman Judith 
Published: November 2019

Abstract
Early identification of high risk patients is warranted in high tumor burden or advanced follicular lymphoma. In this regard post induction FDG-PET/CT and parameters obtained from quantitative baseline FDG-PET such as total metabolic tumor volume (TMTV) have been proposed as prognostic tools (J Clin Oncol, 2016, in press). It has been shown recently that the presence of large TMTV>510cm3 can help to early detect patients who relapse within two years of therapy but TMTV is not yet used routinely. The aim of this study was to assess the prognostic impact of SUVmax measured on baseline FDG-PET/CT as an index of tumor proliferation and its added value to other prognostic parameters in this population.
Methods: A pooled analysis of patient data and centrally reviewed baseline PET/CT scan for 181 patients with high tumor burden follicular lymphoma receiving R-chemotherapy within three prospective trials was performed (PET-FOLL and PRIMA from the LYSA, FOLL05 from the FIL), (Lancet Haematol, 2014). 82% of patients received R-CHOP, 14% R-CVP, 4% R-FM and 16 patients received R maintenance. Baseline SUVmax was computed on quality controlled PET/CT scan and the optimal cut-off for survival prediction was determined by Receiver Operating Curves and X-tile analysis. Multivariate analysis stratified by study were performed between SUVmax and the different components of FLIPI2 and between SUVmax and baseline TMTV.
Results: Median age was 55 years; 92% of patients had stage III/IV disease; 37% had FLIPI 3-5; 31% had FLIPI2 3-5. With a median follow up of 64 months, 5y-PFS was 55% and 5y-OS 92%. Only two patients had disease transformation. Median SUVmax was 10 (Q1-Q3:7-14). There was no correlation between the SUVmax and histological grade. The optimal SUVmax cut-off was 9.4. Surprisingly the 47% of patients with a SUVmax ≤9.4 had markedly inferior PFS. 5y PFS was 47.4% vs. 62.4% (HR= 1.62, p=0.032). On multivariate analysis between SUVmax, age, Longest diameter of Largest involved lymph node LodLin> 6cm, positive Bone marrow biopsy and β2 microglobulin, only SUVmax (HR=1.81, p=0.04) and β2 microglobulin (HR=2.48, p=0.006) were independent predictors of PFS (Table1). When SUVmax and β2 microglobulin were combined they identified three risk groups: low SUVmax and high β2 microglobulin with 5y-PFS 32% (HR=3.95, p=0.0005), low SUVmax or high β2 microglobulin with 5y-PFS 54% (HR=2.29, p=0.018) and high SUVmax and low β2 microglobulin with 5y-PFS 73 % (Fig1). In multivariate analysis TMTV>510cm3 remains the only significant predictor against SUVmax≤9.4. There was no difference in the SUVmax values in high or low TMTV groups and similar % of high and low TMTV in low and high SUVmax groups. Furthermore, the 17% of patients with SUVmax≤9.4 and TMTV>510cm3 had a 22% 5y PFS vs 67.4% for the 40% of patients with SUVmax>9.4 and TMTV≤510cm3 (HR=3.96, p<0.001).
Conclusions: SUVmax and β2 microglobulin are readily available parameters at staging. A low SUVmax observed on a baseline PET or an elevated β2 microglobulin is predictive of progression in patients with high tumor burden follicular lymphoma having received R-chemotherapy. The risk of progressive disease increases when patients have both these risk factors, and such patients deserve special consideration in treatment planning and follow-up.
Figure 1. Figure 1.

Disclosures
Dupuis: janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Luminari:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.