Number of Circulating t(14;18) Tumor Cells at Diagnosis Is Related to, but Add to the Prognostic Value of Metabolic Tumor Burden in Follicular Lymphoma

Beside the rare true leukemic forms of follicular lymphoma (FL), low levels of circulating tumor cells (CTC) are detected by PCR in the vast majority of FL patients at diagnosis. By a regular recirculating process, those CTC could reflect the total solid tumor mass. Alternatively, they could represent a subpopulation of tumor cells with distinct molecular profile including adhesion molecules and, as such, could add to the prognostic value of solid tumoral mass previously reported in FL (Dupuis, JCO 2013). < style="text-align: justify;">In order to address these issues, we retrospectively selected FL patients treated in our institution between 2007 and 2014 who were simultaneously evaluated for both t(14;18) cells in peripheral blood (PB) and FDG-PET/CT tumor mass at diagnosis or at relapse.  Absolute quantification of t(14;18) positive cells was performed using quantitative droplet digital PCR (ddPCR). Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were calculated from FDG-PET/CT, and baseline clinical characteristics and outcomes were collected. < style="text-align: justify;">One hundred fourteen patients fulfilled the inclusion criteria. Using a routine 10^-4 sensitive biomed 2 t(14;18) PCR assay, 75 had a positive PCR, either in peripheral blood alone (n=37), in peripheral blood and tumor biopsy (n=27) or in tumor biopsy but not PB (n= 11). Absolute quantitative ddPCR was performed for the 56 t(14;18) MBR+ patients. Clinical characteristics are given in Table 1. Median CTC value (number of t(14;18) positive cells out of total peripheral blood nucleated cells) was 1.6 10^-3 (range 0-0.96), with only 5 CTC (-) patients and 13 patients with >10% CTC . Median TMTV was 267 cm³ (range 4.61-1900) and median TLG was 1473 (range 10.24-5912). A positive correlation was found between number of CTC and TMTV (R² = 0.49; P<0.001; Fig.1) and to a lesser extend with TLG (R² = 0.38; P<0.001). With a median follow-up of 32 months, OS of FLIPI 0-2 patients was 100% vs 87% for FLIPI 3-4 patients (p=0.003). A number of CTC > 6%, TMTV > 432 cm³ and TLG > 2717 tend to be associated with poorer OS (Fig. 2). The combined presence of > 6% CTC and TLG > 2717 allowed to identify a group of patients with 3-year OS of 71%, compared with 100% when both criteria were negative or dissociated (P= 0.01) (Fig. 2). In the subset of 42 patients with an untreated and untransformed FL, incremental prognostic value of circulating mass and metabolic tumor burden remained significant (P=0.03).

       
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