To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B cell lymphoma (DLBCL) in the context of the US Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab (R)-CHOP induction, with or without maintenance rituximab (MR).
Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts.
The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure free survival and overall survival (FFS: relative risk 0.3; P = 0.001; OS: relative risk 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients.
Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher FFS rate at 5 years compared to CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in FFS according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in uni- or multivariable analyses.
In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.