High dose chemoradiotherapy and Asct may overcome the prognostic importance of biologic markers in relapsed/refractory hodgkin lymphoma

INTRODUCTION: Of about 20% of patients with relapsed/refractory Hodgkin lymphoma (HL), approximately half achieve long-term remissions after high-dose chemoradiotherapy and autologous stem cell transplantation (HDT/ASCT). Treatment with a comprehensive program using second-line chemotherapy with ICE (ifosfamide, carboplatin, etoposide) before HDT/ASCT identified a clinical prognostic model, but prognostic biologic markers in relapsed/refractory HL remain unclear. We sought to determine if we could identify such markers, and if our comprehensive second-line program could overcome their significance. METHODS: Pre-ICE biopsy specimens of 191 patients enrolled on 1 of 2 Institutional Review Board-approved clinical trials of HDT/ASCT. We performed immunohistochemistry staining for Bcl-2, Bax, Bim, p53, and interleukin-6. Samples were considered positive if more than 10% of Hodgkin Reed-Sternberg cells stained at any intensity. RESULTS: Ninety-one patients had sufficient tissue available. Forty-eight patients (53%) had an event and 36 (40%) died. Median event-free survival (EFS) was 8.5 years, median overall survival (OS) was not reached, and median follow-up was 8.8 years. Bcl-2 was overexpressed in 37/91 (41%), Bax in 28/65 (43%), Bim in 9/72 (13%), p53 in 38/89 (43%), and interleukin-6 in 58/84 (69%) patients. Overexpression of these biomarkers had no statistically significant association with EFS or OS, except for association of Bim overexpression with inferior OS (P=0.0385). The 3-factor clinical model (B symptoms at relapse, extranodal disease, and complete remission duration of <1 y) remained highly significant (0/1 vs. 2/3 factors) for EFS and OS (P=0.0008 and P=0.0001, respectively). CONCLUSIONS: Despite the evidence that p53 and Bcl-2 overexpression may predict a worse prognosis with initial treatment, it seems that at relapse such overexpression is either not prognostically significant, or that the treatment with ICE and HDT/ASCT overcomes its significance. Subsequent studies should further address the role of Bim in both initial and relapsed/refractory settings.