The Importance of Molecular Phenotype in Predicting Overall Survival in Patients with Relapsed or Primary Refractory DLBCL Treated with Second-Line Chemotherapy and ASCT.
Authors: Moskowitz Craig H. , Kewalramani Tarun , Hamlin Paul , Nimer Stephen D. , Zelenetz Andrew D. , Teruya-Feldstein Julie 
Published: April 2020

From 1993–2001 we treated 186 patients (pts) 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). Pts with chemosensitive disease received high dose chemoradiotherapy (HDT) and ASCT. In the context of these studies we reported the following: Pts achieving a complete response to ICE, pre-HDT/ASCT, have an improved overall survival (OS) (Journal of Clinical Oncology 1999, 12: 3776–85), pts with chemosensitive primary refractory disease have the same OS as relapsed pts (Blood 2000, 96: 2399–2404); and the second-line age-adjusted IPI (SAAIPI) predicts OS (Blood 2003, 102: 1989–96). In an attempt to further delineate prognostic factors in this setting tissue microarrays (TMA) were constructed as previously described by our group (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 pts. 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+ (&lt;50% tumor cells positive) and 3–4+ (&gt;50% tumor cells positive). For all other markers, a positive score was based on &gt;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; we also evaluated whether the MP of the pre-ICE biopsy specimen could predict survival in pts 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 Blood2004; 103: 275–282). At a median follow-up of 6.5 years the the actuarial OS is 39.7% and 49% for patients receiving HDT/ASCT. In this subset of 88 pts, we confirmed that the SAAIPI predicted outcome: good risk pts having an OS of 52% and poor risk 26%, p&lt;0.001 and pts with primary refractory disease that received HDT/ASCT had the same OS 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 OS of GC pts vs. non-GC pts as analyzed by intent to treat is 38.3% and 42.9% respectively, p=0.7; and for the pts who received HDT/ASCT (53.4% vs. 54.5%, p=.97)

Conclusion: A non-GC "molecular phenotype" does not predict for a poor outcome in pts with relapsed or primary refractory DLBCL treated with ICE-based SLT followed by HDT/ASCT.

MARKER ANALYSIS FOR 88 PTS WITH RELAPSED/REFRACTORY DLBCL

MARKER OVERALL SURVIVAL P VALUE MIB 1 0–2+ 38.6% MIB 1 3–4+ 41% 0.9 MUC 1 neg. 39.2% MUC 1 pos. 40.6% 0.5 MDR neg. 34.5% MDR pos. 40.6% 0.6 p53 neg. 39.5% p53 pos. 41% 0.6 Bcl-2 neg. 37.1% Bcl-2 pos. 42.2% 0.9 CD10 pos. 39.7% CD10 neg. 40% 0.8 bcl-6 pos. 33% bcl-6 neg. 44% 0.5 MUM 1 neg. 36% MUM 1 pos. 41.8% 0.8