STAT3 Expression and Clinical Implications In De Novo Diffuse Large B-Cell Lymphoma: A Report From The International DLBCL Rituximab-CHOP Consortium Program

Expression of signal transducer and activator of transcription 3 (STAT3) in de novo diffuse large B-cell lymphoma (DLBCL) has not been studied broadly and the prognostic value of STAT3 expression in DLBCL is controversial.

The study group included 876 de novo DLBCL patients. All patients were treated with rituximab, cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone (R-CHOP). Cases excluded from the study group included large cell transformation from low-grade B-cell lymphoma, primary cutaneous large B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary DLBCL of the central nervous system and cases associated with Epstein-Barr virus or human immunodeficiency virus. Immunohistochemical (IHC) studies for several biomarkers were performed using fixed, paraffin embedded sections of tissue microarrays. Fluorescence in situ hybridization (FISH) for BCL2, BCL6, MYC, and TP53 were performed andTP53 was also sequenced Gene expression profiling (GEP) was performed on 500 cases and the cell of origin (COO) classification was determined by GEP (gold standard) and immunohistochemistry.

STAT3 was positive in 240 (32.9%) patients, including 133 men and 107 women. The median age of STAT3+ DLBCL patients was 65 years (range, 21-93) and was similar to STAT3- DLBCL patients (63, range 12-95). B symptoms (44.4% vs. 35.2%, P=0.021) and advanced stage (60.5% vs. 52.1%, P=0.035) were more commonly present in STAT3+ DLBCL compared with STAT3- DLBCL patients. Other clinical characteristics were similar between the groups. STAT3+ DBLCLs were more often activated B-cell (ABC) type than STAT3- DLBCLs (61.8% vs. 41.1%, P<0.001). STAT3+ DLBCLs more often expressed MYC (76.7% vs. 56.5%, P<0.001), p50 (43.3% vs. 34.1%, P=0.018), and p65 (33.9% vs. 25.3%, P=0.017) than STAT3- DLBCLs. c-Rel, however, was less commonly expressed in STAT3+ DLBCL (18.9% vs. 27.2%, P=0.018). Expression of BCL2 was similar between the two groups. Genetic aberrations involving BCL2 (10.9%), MYC (7.6%) and TP53 deletion (8.1%) by FISH were uncommon. Aberrations of BCL6 were present in 24.6% of STAT3+ DLBCL. TP53 mutation was found in 27 patients (20.1%). The frequency of genetic aberrations by FISH was similar in the STAT3+ and STAT3- DLBCL groups. Patients with STAT3+ versus STAT3- DLBCL had similar OS (P=0.494) and PFS (P=0.224). When looking at all DLBCL cases divided into GCB versus ABC type, STAT3 expression did not predict survival in the GCB (OS, P=0.945 and PFS, P=0.604) or ABC types (OS, P=0.211 and PFS, P=0.079, respectively). In multivariate analysis, STAT3 expression did not show an increased hazard ratio (HR 0.806, 95% CI 0.578-1.125, P=0.205).

STAT3 is expressed in approximately 1/3 of de novo DLBCLs. STAT3 expression is associated with B symptoms, advanced stage of disease, ABC type, and expression of MYC. Expression of p50 and p65 are more frequently expressed in STAT3+ DLBCL, illustrating activated NF-κB through canonical pathway. C-Rel is less commonly expressed in STAT3+ DLBCL, suggesting p65 is the principal partner for p50. Genetic aberrations are rare. Although STAT3 expression is associated with several adverse prognostic parameters, it does not confer inferior OS and PFS in DLBCL overall, suggestive of the presence of yet unidentified putative tumor suppressive functions in STAT3+ DLBCL patients.

Winter:Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents & Royalties.