A High Tumor-Associated Macrophage Content Predicts Favorable Outcome in Follicular Lymphoma Patients Treated with Rituximab and Cyclophosphamide-Doxorubicin-Vincristine-Prednisone

Abstract

Purpose: Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy. The aim of this study was to determine how combination of rituximab with chemotherapy influences TAM-associated clinical outcome. Experimental Design: Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with rituximab and cyclophosphamideAdriamycin-vincristine-prednisone regimen. Of them, 71received therapy at diagnosis and 25 at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months. Fourty-five patients previously treated with chemotherapy served as a control group. Results: Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients (P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was not reached for patients with high TAM content compared with 45 months for patients with low TAM scores (P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS, 97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did not correlate with outcome. Conclusions: The data suggest that highTAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.Follicular lymphoma (FL) is the second most common subtype of all non -Hodgkin lymphomas accounting for f20% of all adult cases in the western world. FL arises from B cells in the germinal center of lymphoid tissue. It is an indolent and a chemotherapy-sensitive disease, which is, however, considered rarely curable due to its propensity to relapse. Recently, however, a significant improvement of the outcome of patients has been obtained by combining a monoclonal anti-CD20 antibody, rituximab, with induction chemotherapy (1 -3), or by prolonging the remission with rituximab maintenance therapy (4, 5). Despite the advances, response to treatment varies substantially among individual patients and outcome is often unpredictable. Treatment is also costly. These facts raise the need to identify more accurately the patients who benefit from immunochemotherapy.In FL, a specific Follicular Lymphoma International Prognostic Index (FLIPI) has been proposed (6). Although FLIPI was developed before rituximab was established in the treatment of FL, it was recently shown to be a useful predictor of the outcome also in response to rituximab and cyclophosphamideAdriamycin-vincristine-prednisone (R-CHOP) regimen (7). In estimating the prognosis of FL, FLIPI seems to distrib...

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