The Importance of Molecular Phenotype in Predicting Overall Survival in Patients with Relapsed or Primary Refractory DLBCL Treated with Second-Line Chemotherapy and ASCT- ASH Study

The American Society of Haematology (ASH) had its annual meeting earlier this month. Haematologists from around the world gathered at the San Diego Convention Centre to provide a forum for discussing critical issues in haematology. Nearly 20,000 clinicians, scientists, and others attended the four-day meeting, which consisted of an educational program and cutting-edge scientific sessions. The following was one of the presentations given at the meeting.

From 1993-2001, researchers from the Memorial Sloan Kettering Cancer Centre, NY, USA treated 186 patients with relapsed or primary refractory diffuse large B cell lymphoma (DLBCL) on IRB-approved clinical trials with ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy (SLT).Patients with chemosensitive disease received high dose chemoradiotherapy (HDT) and ASCT. In this context, patients achieving a complete response to ICE, pre-HDT/ASCT, have an improved overall survival (Journal of Clinical Oncology 1999, 12: 3776-85). Patients with chemosensitive primary refractory disease have the same overall survival as relapsed patients (Blood 2000, 96: 2399-2404); and the second-line age-adjusted IPI (SAAIPI) predicts overall survival (Blood 2003, 102: 1989-96).In an attempt to further delineate prognostic factors in this setting, tissue microarrays (TMA) were constructed as described in one of the researchers previous publications (Hum Pathol 2002: 968-74). All patients had a repeat biopsy prior to initiating SLT confirming active DLBCL; this sample was used for the TMA. Adequate tissue was available on 88 of these patients. TMA sections were stained for the following immunohistochemical markers and analyzed: MIB-1 (Ki-67), MUC1, MDR, p53, bcl-2, CD10, bcl-6, and MUM1. MIB-1 was scored in quartiles and for statistical purposes grouped as 1-2+ (<50% tumor cells positive) and 3-4+ (>50% tumor cells positive). For all other markers, a positive score was based on >20% of tumor cells staining positive. The ‘molecular phenotype'(MP), germinal center (GC) vs non-GC has an impact on progression-free survival in untreated DLBCL; researchers also evaluated whether the MP of the pre-ICE biopsy specimen could predict survival in patients with relapsed or primary refractory DLBCL undergoing SLT/HDT/ASCT. A GC phenotype is defined as either CD10 positive or bcl-6 positive and MUM 1 negative (Hans et al Blood 2004; 103: 275-282).At a median follow-up of 6.5 years the actuarial overall survival is 39.7% and 49% for patients receiving HDT/ASCT. In this subset of 88 Patients, researchers confirmed that the SAAIPI predicted outcome: good risk patients having an overall survival of 52% and poor risk 26%, p<0.001 and patients with primary refractory disease that received HDT/ASCT had the same overall survival as those with relapsed disease. None of the TMA markers impacted outcome; nor was there a difference in outcome based upon GC vs. non-GC TMA MP. The overall survival of GC Patients vs. non-GC Patients as analyzed by intent to treat is 38.3% and 42.9% respectively, p=0.7; and for the patients who received HDT/ASCT (53.4% vs. 54.5%, p=.97)Researchers concluded that a non-GC 'molecular phenotype' does not predict for a poor outcome in patients with relapsed or primary refractory DLBCL treated with ICE-based SLT followed by HDT/ASCT.(Source: American Society of Haematology (ASH): Blood, Volume 104, issue 11, November 16, 2004.)