A Study on nm23-H1 Expression in Hodgkin Lymphoma That Was Treated with BEACOPP Therapy

Abstract 4861

Approximately 8∼10% of all lymphoma patients in Japan have classical Hodgkin's lymphoma (CHL). On the other hand, in European and North American populations, CHL comprises 25% of all lymphoma patients. The treatment strategy of CHL is currently determined by the disease stage. The ABVD (doxorubicin, bleomycin, vindesine and dacarbazine) regimen is the standard treatment for CHL. Recently, therapies for CHL have improved, at least partly because the choices of treatment have broadened to include radiotherapy, the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) regimen, and Stanford V regimen. However, it is important to be able to predict the prognosis and make a stratified treatment plan that attains a long remission period with the initial treatment. nm23-H1 was originally identified as a protein that was expressed at a lower level in metastatic cancer cells. The nm23 genes play critical roles in cellular proliferation, differentiation, oncogenesis, and tumor metastasis. We previously reported that the serum nm23-H1 level was significantly higher in patients with aggressive lymphoma than in healthy controls, and that a high nm23-H1 level was associated with poor prognosis in patients with aggressive lymphoma. In the present study, we examined nm23-H1 expression in CHL that was treated with BEACOPP therapy. The subjects were 49 CHL patients who underwent BEACOPP therapy and in whom markers could be analyzed. Patients aged between 18 and 69 years who had an International Prognostic Score (IPS) of 3∼5, were eligible for this study. Of the 49 patients with CHL, 26 had nodular sclerosis (NS) and 23 had mixed cellularity (MC). We evaluated CD15, CD20, CD30, and nm23-H1 expression by immunohistochemistry. We counted 30 Hodgkin and Reed-Sternberg (H-RS) cells and if 20 (67%) or more of the 30 cells were positive for nm23-H1, the specimen was considered to be positive for cytoplasmic nm23-H1. The presence of Epstein-Barr virus (EBV) small RNAs (EBER) was determined by in situ hybridization using EBV-encoded small nuclear early-region oligonucleotides on formalin-fixed, paraffin-embedded sections. EBER was harbored in 56%(13/23) of the MC patients and in 8%(2/26) of the NS patients, showing a significant difference (p=0.0003). nm23-H1 expression was observed a significantly lower percentage of MC patients than NS patients [30%(7/23) vs. 58%(15/26), p=0.03]. nm23-H1 expression was significantly associated with the presence of stage IV. There were no significant associations between nm23-H1 expression and age, gender, serum LDH level, IPS, WBC count, serum albumin level, or hemoglobin level. The nm23-H1-positive rate among the patients who achieved complete response was 86%(19/22), while the nm23-H1-positive rate among those who failed to do so was 100%(27/27). Among all 49 CHL patients, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 92% and 84%, respectively. The patients were divided into 2 groups according to positivity or negativity for EBER. The 3-year PFS rate of the EBER-positive and -negative groups was 66.7% (n=15) and 91.3% (n=34), respectively (p=0.017). Thus, the EBER-positive group showed a significantly poorer prognosis than the EBER-negative group. As for IPS, the 3-year PFS of the IPS ³4 group (n = 20) was 89% and that of the IPS=3 group (n = 29) was 100%, indicating that the high-risk group showed significantly poorer prognosis (p = 0.011).When the patients were divided into the nm23-H1-positive and -negative groups, the 3-year OS rate was significantly lower in the nm23-H1-positive group (81%) than in the nm23-H1-negative group (100%) (p=0.02). Among patients with CHL who underwent BEACOPP therapy, patients with nm23-H1 expression had a significantly poorer prognosis than patients without nm23-H1 expression. These results suggest an important role for nm23-H1 in malignant progression and a potential therapeutic target in CHL.