Peripheral Blood CD3+CD4+ and CD3−CD56+ Cell Counts and Circulating Lymphoma Cells Are Significant Predictors of Overall Survival in Newly Diagnosed Follicular Lymphoma.
Authors: Shafer Danielle , Smith Mitchell R. , Litwin Samuel , Li Tianyu , Borghaei Hossein , Al-Saleem Tahseen I. 
Published: April 2020

Abstract
BACKGROUND: Interaction between the immune system and follicular lymphoma (FL) is well recognized from immunohistochemical as well as microarray studies, but is not yet fully elucidated. A recent report suggested that a higher absolute lymphocyte count (ALC) predicted a longer time to progression and improved response to rituximab in FL (Behl et al, Br J Haem2007). The GELA group reported a correlation between peripheral blood natural killer cell count and event free survival in diffuse large B cell lymphoma (Plonquet et al Ann Oncol2007). The influence of lymphocyte subsets in the peripheral blood (PB) on FL outcome has not been reported.
PATIENTS AND METHODS: We retrospectively analyzed the immunophenotype from peripheral blood flow cytometry (PBFC) at Fox Chase Cancer Center in FL patients (pts). We identified 127 pts (82 newly diagnosed and 45 previously treated). We recorded the presence or absence of circulating monoclonal B cells (CLC) and survival in all as well as a complete PBFC panel in &gt; 90% of pts. FLIPI and IPI scores were calculated from data at the time of diagnosis. Overall survival and time to treatment from date of original diagnosis and from date of PBFC were analyzed in relation to ALC, CLC, the lymphocyte subsets CD3+CD4+, CD3+CD8+, CD3−CD56+/CD16+ (NK cells) and FLIPI and IPI scores. A low CD4 count was defined as &lt;500 cells/mm3, a low NK cell count as &lt;150 cells/mm3 and a low ALC as &lt;1500 cells/mm3.
RESULTS: There were 63 females and 64 males; median age at presentation was 56 yrs (range 31–88). Median follow up intervals from original diagnosis and from PBFC were 46 months (range 3.5 – 207) and 24 months (range 0.7–138), respectively. This abstract deals principally with the 82 newly diagnosed pts. Median follow up in the newly diagnosed subset was 27.8 months (range 0.7 to – 138); thirty-five pts were subsequently treated, and 47 pts remained under observation. FLIPI scores at diagnosis were: low - 48 pts, intermediate - 25, high - 7 and unknown - 2. IPI scores were: low - 52 pts, low-intermediate - 24, high-intermediate/high - 4 and unknown - 2. CLC were present in 21% of pts. At last follow up, 74 pts were still alive. By univariate analysis, the most significant predictors for inferior overall survival (OS) from time of PBFC were low CD4 count (P = 0.03), low NK cell count (P = 0.02), and presence of CLC (P = 0.03). There was insufficient power for significance in multivariate analysis. At last follow up, survival for the low vs. high CD4 and NK cell groups was 85% vs. 97% and 85% vs.98%, respectively. FLIPI and IPI scores, low ALC, and low CD8 did not correlate with OS from time of diagnosis or time of PBFC. With respect to time to initial treatment, only a low ALC (P&lt;0.001) and FLIPI (P&lt;0.001) were significant. In multivariate analysis for OS of all 127 pts, low NK cell count remained significant (P = 0.03), while low CD4 count was marginally significant (P = 0.08).
CONCLUSION: Analysis of PB lymphocytes by PBFC has prognostic value in previously untreated FL pts. Low CD4 and NK cell counts as well as the presence of CLC are the most significant predictors for OS in newly diagnosed FL. Our findings suggest the importance of an intact immune system. They merit further prospective studies to ascertain the impact of treatment on subsets of pts with specific immunophenotypes and may prove useful in FL management.