Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma

Abstract

Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline F-fluorodeoxyglucose-positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs ( < .0001) and cfDNA ( < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm ( = .0004), CTCs >0.0018 PB cells ( = .03), or cfDNA >2550 equivalent-genome/mL ( = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.

Genetic alterations in B cell lymphoma subtypes as potential biomarkers for non-invasive diagnosis, prognosis, therapy, and disease monitoring

“…From a precision medicine perspective, cfDNA genotyping may assist clinicians in choosing the most suitable option for targeted therapy through facilitated detection of individual genetic subclones responsible for relapse in DLBCL patients. There are other recent studies that evaluated plasma cfDNA levels in DLBCL (Kurtz et al, 2018), addressing whether it can predict or monitor therapy response or if it can predict tumor burden or prognosis of FL cases (Delfau-Larue et al, 2018). Using droplet digital PCR, Alcaide et al detected previously known mutations (e.g., EZH2 Y641 and STAT6 D419) in circulating tumor DNA in major B cell NHL subtypes (Alcaide et al, 2016).…”

How I manage patients with follicular lymphoma

“…While promising, TMTV has limitations that prohibit its routine use in daily practice. Specialized software and training are required to calculate TMTV and there are differing cut‐offs among various studies depending on lymphoma subtype (Delfau‐Larue et al , ).…”

“…The m7‐FLIPI is not currently used in standard practice but is a promising tool for future application given the use of formalin‐fixed paraffin‐embedded tissue for assessment of gene mutations. Both the m7‐FLIPI and the PRIMA‐PI require further validation in future studies, in the era of novel therapies, possibly in combination with other parameters, such as PET scan or minimal residual disease analysis of circulating tumour DNA (Delfau‐Larue et al , ).…”

“…High TMTV (cut off of 510 cm 3 or greater) on PET additionally has poor prognostic implications at the time of diagnosis (Meignan et al , ). Circulating tumor and cell free DNA has been strongly correlated to baseline PET TMTV and inferior PFS as well (Delfau‐Larue et al , ). These prognostic biomarkers will play a greater role over time in helping distinguish patient risk at diagnosis and end of treatment.…”

Genomic profiling of plasma circulating tumor DNA reveals genetics and residual disease in extranodal NK/T-cell lymphoma

“…Clinical application of ctDNA has been performed in multiple types of lymphoma, such as diffuse large B-cell lymphoma (DLBCL), classical HL, follicular lymphoma and peripheral T-cell lymphoma (Delfau-Larue et al, 2018;Roschewski et al, 2015;Scherer et al, 2016;Spina et al, 2018;Suehara et al, 2018) by using immunoglobulin next-generation sequencing (Ig-NGS), T-cell receptor gene next-generation sequencing (TCR-NGS) and cancer personalized profiling sequencing (CAPP-Seq).…”