High Dose Chemoradiotherapy and ASCT Can Overcome the Prognostic Importance of Bcl-2, Bim, and p53 in Relapsed/Refractory Hodgkin’s Lymphoma.

Introduction: Approximately twenty percent of patients with Hodgkin’s lymphoma (HL) relapse or have primary refractory disease. About 50% of these patients achieve long-term remissions after high-dose chemoradiotherapy and autologous stem cell transplantation (HDT/ASCT). At MSKCC, ICE (ifosfamide, carboplatin, etoposide) was incorporated as second-line chemotherapy prior to HDT/ASCT in a comprehensive treatment program. In addition to chemosensitive disease, a clinical prognostic model that emerged from this study identified 3 risk factors - B symptoms at relapse, extranodal disease, and complete remission duration of less than 1 year (Blood. 2001 Feb 1;97(3):616–23). This model was used to intensify treatment according to the number of risk factors, with stratification overcoming the significance of poor prognostic features (Blood. 2003 Nov 16;102(11), abstract #403). Methods: To further identify important prognostic factors, we evaluated pre-ICE biopsy specimens of patients enrolled on one of 3 IRB-approved clinical trials of HDT/ASCT. Prior studies showed that overexpression of bcl-2 and p53 have negative impact on outcome with primary therapy. We sought to determine if our comprehensive second-line program could overcome these poor prognostic features. We performed immunohistochemistry staining for bcl-2, bim (a bcl-2 family marker), and p53; samples were considered positive if any Reed-Sternberg (RS) cells stained for bcl-2 or bim, and if more than 50% stained for p53, at any staining intensity. Results: Seventy one patients had sufficient tissue available. Thirty five patients (49%) had disease progression and 28 (39%) died. Median PFS was 4.8 years, median OS was not reached, and median follow-up was 5.7 years. Bcl-2 was overexpressed in 19(27%), bim in 22 (32%), and p53 in 20 (29%) patients. Expression of bcl-2, bim, or p53 had no significant association with PFS or OS. Five-year PFS rates for positive vs. negative cases were 52.6% vs 50% for bcl-2, 54.5% vs 50% for bim, and 50% vs 51% for p53 (all p=NS). The 3 factor clinical model (B symptoms at relapse, extranodal disease and complete remission duration of less than 1 year) remained highly significant (0/1 vs 2/3 factors) for PFS and OS (p=0.002 and p=0.0003, respectively). Conclusion: Despite the evidence that p53 and bcl-2 overexpression may predict a worse prognosis with initial treatment, it appears that the approach of incorporating ICE and HDT/ASCT may overcome the significance of these biological markers at relapse. Further studies will focus on other pathways that are thought to play a role in relapsed/refractory HL outcomes. Bim is a novel pro-apoptotic marker from the bcl-2 family that is expressed on RS cells and suggests a role in the pathogenesis of HL. Future studies will focus on its role in both initial and relapsed/refractory setting.