Numbers of Lymphoma Associated Macrophages (LAMS) and Regulatory T-Cells (Tregs) in Follicular Lymphoma (FL) Patients (pts) Treated with and without Monoclonal Antibody (MoAb)-Containing Therapy Do Not Correlate with Overall Survival (OS): A Study from the Southwest Oncology Group (SWOG).
Authors: Sweetenham John William , Hsi Eric , Goldman Bryan , LeBlanc Michael , Tubbs Raymond R. , Cook James R. , Press Oliver W. , Fisher Richard I. , Rimsza Lisa M. 
Published: April 2020

Introduction: Conflicting results have been reported for the prognostic value of LAMs and Tregs in FL. A recent study from the SWOG suggested that survival for pts with FL has improved in the last 30 years, possibly due to the introduction of MoAb-based therapy. We examined the prognostic significance of LAMs and FOX-P3-positive Tregs using tissue microarrays (TMAs) from pts entered onto SWOG studies 8809 (no MoAb) and 9911chemotherapy followed by (including 131I-tositumomab).

Pts & methods: Adequate tissue samples were identified from 87 pts on SWOG 8809 and 47 on 9911. Pt characteristics were as follows: 8809: median age - 47.4 yrs (26.1 – 69.4), male 53%, Follicular Lymphoma International Prognostic Index (FLIPI) score: 1–36%, 2–39%, 3–21%. 9911: median age - 49.9 (22.9 – 66.8), male-60%, FLIPI score: 1–36%, 2–45%, 9–19%. The pts with available tissue were comparable with those who did not have available tissue for clinical prognostic factors. Archival blocks were reviewed to confirm FL and to assess for preparation of TMAs containing two 1mm diameter cores per case. Automated immunostaining for CD68 (PGM1) and FOXP3 (236A/E7) was performed. Intrafollicular (IF) and extra follicular (EF) LAMs were quantitated by manual count (5 1000x high power fields [hpf]). FOXP3 was scored for pattern (follicular/perfollicular vs. other) and number/5 hpf .LAM and Treg numbers/patterns were correlated with OS Marker levels were categorized by medians, 3rd quartiles and as continuous variables. Survival differences by marker level/pattern were assessed within each study population by Cox regression.

Results: Pt characteristics did not differ by SWOG study. Hazard ratios with 95% confidence intervals for OS according to FOX-P3 and CD68 staining are shown in table 1. LAMS were not associated with OS, except for IF LAMS in S9911. Levels or pattern of FOX-P3 staining were not associated with OS.

Conclusion: Levels of LAMs and Tregs were not predictive of overall survival in FL pts on SWOG trials before and after the introduction of anti-CD20 radio-immunotherapy (RIT). While IF LAMs in pts receiving RIT may be associated with shorter OS, the number of cases/events is too small for firm conclusions. Further studies are required to determine the prognostic value of these biomarkers in FL patients receiving anti-CD20 MoAb-containing therapies.

Hazard ratios (95% CI) for OS for biomarker levels S8809 S9911 Overall * p&lt;0.05 FOX-P3 (follicular vs other) 0.66 (0.29, 1.46) 0.95 (0.11, 8.10) 0.69 (0.33, 1.46) FOX-P3 (above median vs below) 1.30 (0.66, 2.58) 0.60 (0.11, 3.26) 1.16 (0.62, 2.17) EF LAM (above median vs below) 1.24 (0.59, 2.61) 0.70 (0.16, 3.11) 1.11 (0.56, 2.18) EF LAM (above 3rd quartile vs below) 1.12 (0.42, 2.94) 0.64 (0.13, 3.32) 0.96 (0.41, 2.23) IF LAM (above median vs below) 0.79 (0.35, 1.76) 5.33 (1.03, 27.51)* 1.22 (0.58, 2.57) IF LAM (above 3rd quartile vs below) 1.38 (0.62, 3.06) 2.24 (0.43, 11.56) 1.50 (0.72, 3.11)