Originally published as JCO Early Release 10.1200/JCO.2007.12.8298 on December 17 2007

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High Numbers of Tumor-Associated Macrophages Have an Adverse Prognostic Value That Can Be Circumvented by Rituximab in Patients With Follicular Lymphoma Enrolled Onto the GELA-GOELAMS FL-2000 Trial

Danielle Canioni, Gilles Salles, Nicolas Mounier, Nicole Brousse, Marie Keuppens, Frank Morchhauser, Thierry Lamy, Anne Sonet, Marie-Christine Rousselet, Charles Foussard, Luc Xerri

From the Department of Pathology, Assistance Publique-Hopitaux de Paris, Hôpital Necker-Enfants Malades; Université Paris-Descartes, Paris; Department of Hematology, Hospices Civils de Lyon; Université Lyon 1, Lyon; Department of Hematology, Centre Hospitalo-Universitaire, Nice; Department of Hematology, Centre Hospitalier, Lille; Department of Hematology, Centre Hospitalier, Rennes; Departments of Pathology and Hematology Hôpital d'Angers, Angers; Department of Bio-Pathology, Institut Paoli-Calmettes; Université de la Méditerranée, Marseille, France; and Department of Hematology, Hopital Universitaire de Mont-Godinne, Yvoir, Belgium

Corresponding author: Danielle Canioni, MD, Department of Pathology, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015, Paris, France; e-mail: danielle.canioni{at}nck.ap-hop-paris.fr

Purpose: High amounts of intratumoral macrophages have been shown to correlate with poor prognosis in patients with follicular lymphoma (FL) treated with chemotherapy without rituximab. We tried to establish whether intratumoral macrophage count (MC) definitely is able to predict the outcome of FL patients in the rituximab era.

Patients and Methods: We analyzed immunohistochemical CD68 expression in 194 FL patients from the FL-2000 trial, randomly assigned to receive cyclophosphamide, doxorubicin, etoposide, prednisolone, and interferon (CHVP-I) or rituximab plus CHVP-I. Immunohistochemistry was performed on paraffin sections using anti-CD68 KP1 antibody, and stained macrophages were scored on high-power field (hpf) in either intrafollicular (IF) or extrafollicular (EF) areas.

Results: For IF MC, the best cutoff point was estimated at 10 macrophages/hpf. Low IF MC was significantly associated with a better event-free survival (EFS; P = .011). However, this effect was observed only in the CHVP-I arm (P = .012) and not in the rituximab plus CHVP-I arm. Using a cutoff of 15 IF MC, we found no significant association with EFS. For EF MC, fewer than 22 macrophages/hpf were associated with better EFS in the CHVP-I arm (P = .02) but not in the rituximab plus CHVP-I arm.

Conclusion: These results show that MC can predict outcome of FL patients and that rituximab is able to circumvent the unfavorable outcome associated with high MC.

published online ahead of print at www.jco.org on December 17, 2007.

Supported by the Programme Hospitalier de Recherche Clinique (Hospices Civils de Lyon, PHRC 2000-081) and the Ligue Nationale Contre le Cancer.

Presented in part at the Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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