Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low-and high-risk groups. To determine how combination of rituximab with chemotherapy influences GCassociated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P ؍ .012; FFS, 59% vs 30%, P ؍ .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P ؍ ns; FFS, 68% vs 63%, P ؍ ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low-and intermediate-risk groups (OS, 84% vs 63%, P ؍ .030; FFS, 79% vs 52%, P ؍ .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC-and non-GC phenotypes in DLBCL. (Blood. 2007;109: [4930][4931][4932][4933][4934][4935]
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...
impact in DLBCL. [14][15][16][17] Of the macrophages, classically activated M1 type TAM have been described as "good", acting to prevent the growth of tumor tissue, whereas the alternative M2 type TAM may have an opposite effect promoting angiogenesis and tumor development. [18][19][20] Importantly, however, studies in follicular lymphoma have demonstrated that the prognostic significance of the tumor microenvironment and especially macrophages is highly dependent on a given therapy. [21][22][23] In the present study, we investigated how the combination of rituximab with chemotherapy influences non-malignant inflammatory cell-associated clinical outcome in DLBCL. Among all studied markers for macrophages, dendritic, and lymphoid cells, we found that pretreatment gene expression of a macrophage marker CD68 and immunohistochemically defined CD68+ TAM content had a positive prognostic impact on the survival of DLBCL patients treated with chemoimmunotherapy, whereas in patients treated without rituximab, CD68 + TAM content was associated with a poor outcome. Methods Patients and samplesThe screening cohort consisted of prospectively collected DLBCL patients who were less than 65 years old and had primary high-risk (age-adjusted IPI score 2-3) disease. They were treated in the Nordic phase II NLG-LBC-04 protocol with dose-dense chemoimmunotherapy followed by systemic central nervous system prophylaxis. 24 The patients in this correlative study represent a subset of patients in the main clinical trial and were selected on the basis of DLBCL histology, the availability of fresh frozen tissue for RNA extraction and exon arrays (gene expression cohort; n=38) and formalin-fixed, paraffin-embedded lymphoma tissue containing adequate material for the preparation of tissue microarrays (TMA; immunohistochemistry cohort; n=59), and the patients' consent to correlative studies. Details of the screening cohort are provided in Table 1, the Online Supplementary Material and Online Supplementary Table S1.The clinical protocol and sampling were approved by Institutional Review Boards, National Medical Agencies and Ethics Committees in Denmark, Finland, Norway and Sweden, and the trial was registered at ClinicalTrials.gov, number NCT01502982.To validate the findings, three independent retrospective series of chemoimmunotherapy-treated DLBCL patients were used. In order to confirm gene expression data, we used RNA sequencing data from 92 patients generated by the Cancer Genome Characterization Initiative (CGCI; dbGaP database applied study accession: phs000532.v3.p1) 25,26 and oligonucleotide-based microarray data from 233 DLBCL patients generated by the Lymphoma/Leukemia Molecular Profiling Project (LLMPP; GEO dataset: GSE10846).10 Both cohorts are subsets of the original study populations treated with a R-CHOP-like regimen based on the availability of complete expression data and clinical information (Online Supplementary Table S2).In order to confirm the immunohistochemical data, an independent population-based series of ...
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