The Poor Prognosis Value of High Intra-Tumoral Macrophages Counts in Follicular Lymphoma Patients Requires Selection of Appropriate Cut-Off and Can Be Circumvented by Rituximab Therapy.
Authors: Canioni Danielle , Salles Gilles , Mounier Nicolas , Brousse Nicole , Keuppens Marie , Morchauser Frank , Fournier Marion , Lamy Thierry , Rousselet Marie-Christine , Foussard Charles , Xerri Luc 
Published: April 2020

Abstract
High amounts of intra-tumoral reactive macrophages have been reported to be associated with a poor prognosis in patients with follicular lymphoma (FL) (Blood2005;106:2169). However, this study has been retrospectively performed in a patients’ population selected before the monoclonal antibody therapeutic area, and has not been confirmed on independent series. To establish whether the intra-tumoral macrophages count (MC) is definitely able to predict the outcome of FL patients, we analysed both immunohistochemical CD68 expression and clinical outcome in patients included in the GELA-GOELAMS FL-2000 trial (ASH-2004; ASCO-2006). Patients between 18 and 75 years of age with high tumor burden FL were randomized to receive either CHVP-I or R-CHVP-I. Among the 358 patients included on the basis of histologically proven FL after reviewing by 3 hematopathologists, 194 had available biopsy specimen. Clinical characteristics of those 194 patients were not different of those of the whole population and median time to event was 43.1 months in 92 pts receiving CHVP-I arm and 54.5 months in the 102 pts receiving R-CHVP-I. Slides were stained with the anti-CD68 KP1 antibody using a standard IHC procedure, then scored on high power field (hpf) (× 400 magnification) by 3 different pathologists.
Analysis of the relative risk of event according to the intra-follicular MC (IF-MC) led us to determine a single cut-off point to categorize the covariate, the best cut-off point being estimated to be 10 macrophages/hpf. The IF-MC was equal or less than 10 intra-follicular KP1+ macrophages/hpf in 53 patients, and more than 10 in 141 patients. With this cut-off of 10, a low MC was significantly associated with a better EFS for all patients (p=0.011). However, this effect was predominantly observed in patients that received CHVP-I (p=0,012, OR) but not in those receiving R-CHVP-I (p=0.15).Multivariate analysis adjusting for 10 IF-MC cut-off (p&lt;0.01), arm (p=0.07) and FLIPI (0.05) confirmed the significant predictive value of the MC for EFS in this population. In contrast, using a cut-off of 15 IF-MC, we found no significant association between MC and patients EFS (p=0.07), in the whole population or in each treatment arm. We extended our observation to the extra-follicular MC (EF-MC), the best cut-off point was estimated at 22 macrophages/hpf, which allowed to separate two equal groups of 97 patients. This cut-off was significantly correlated with EFS in a multivariate analysis adjusting for EF-MC cut-off (p=0.01), arm (p=0.04) and FLIPI (p&lt;0.01). However, the prognostic value for EFS was significant in the group of patients treated with CHVP-I (p=0.02) but not for patients treated with R-CHVP-I. R-CHVP-I was significantly (p=0.01) associated with a better EFS than CHVP-I in high EF-MC patients. These results show that, if appropriate cut-offs are selected, both intra-follicular or extra-follicular MC can predict outcome of FL patients. Moreover, they indicate that rituximab is able to circumvent the poor prognosis associated with high MC in FL patients.