title: High dose chemoradiotherapy and ASCT may overcome the prognostic importance of biologic markers in relapsed/refractory Hodgkin lymphoma.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Persky
authors.forename: Craig H
authors.initials: CH
authors.lastname: Moskowitz
authors.forename: Alexander
authors.initials: A
authors.lastname: Filatov
authors.forename: Rakhee
authors.initials: R
authors.lastname: Saxena
authors.forename: Haiyan
authors.initials: H
authors.lastname: Cui
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000032:analysis; D016190:Carboplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D005047:Etoposide / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006689:Hodgkin Disease / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007069:Ifosfamide / Q000627:therapeutic use; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016879:Salvage Therapy / Q000379:methods*; D014182:Transplantation, Autologous; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D016190:Carboplatin; D007069:Ifosfamide