Tumor-Associated Macrophages Predict Inferior Outcomes in Locally Advanced and Advanced Stage Classical Hodgkin Lymphoma – A Correlative Study from the E2496 Intergroup Trial
King L Tan, David W Scott, Fangxin Hong, Sandra J Horning, Richard I Fisher, Nancy L Bartlett, Lois E Shepherd, Joseph M Connors, Brad S Kahl, Leo I Gordon, Christian Steidl, Randy D Gascoyne. British Columbia Cancer Agency, Vancouver, Canada; Dana Farber Cancer Institute, Boston; Genentech, Inc, South San Francisco; University of Rochester, Rochester; Washington University, St. Louis; NCIC Clinical Trials Office, Kingston, Canada; University of Wisconsin, Madison; Northwestern University, Chicago
Background: Despite advances in chemotherapy for classical Hodgkin lymphoma (cHL), 10-15% of patients still die from progressive or relapsed disease and a similar proportion are likely overtreated. Recently we demonstrated that tumor-associated macrophages are associated with inferior outcome in cHL. We investigated the prognostic significance of macrophages in the E2496 Intergroup Trial.
Design: A tissue microarray was constructed using duplicate 1.5mm cores from diagnostic paraffin blocks including 290 patients with locally advanced and advanced stage cHL treated with ABVD or Stanford V chemotherapy (E2496). CD68 and CD163 IHC were performed and scored by computer image analysis (Aperio) and pathologist scoring. EBV in Hodgkin-Reed-Sternberg (HRS) cells was assessed by in situ hybridization. Optimum thresholds for CD68 and CD163 expression and survival were determined by X-tile. Student's t-tests was used for group comparisons. Survival analysis was determined by Kaplan-Meier method with differences evaluated by log-rank test. Multivariate analysis of survival predictors was performed by Cox regression.
Results: Aperio and pathologist scores were significantly correlated for CD68 (R=0.862, p<0.001) and CD163 (R=0.908, p<0.001). Increased CD68 and CD163 expression were significantly associated with inferior outcomes (Table1). In multivariate analysis with the International Prognostic Score, EBV, CD68 and CD163; both CD68 and CD163 remained significant independent predictors of OS (CD68 p=0.019, CD163 p=0.024), while only CD68 remained a significant independent predictor of FFS (p=0.002). EBV was present in HRS cells in 47/289 cases (16%). CD68 and CD163 expression were significantly increased in cases with EBV-positive HRS cells (Table2).
|5 yr FFS||74%||45%||<0.001||77%||53%||0.002|
|5 yr OS||92%||67%||<0.001||94%||74%||<0.001|