Statins May Prolong Survival in Relapsed DLBCL by Upregulating p27: a Retrospective Case-Control Study.

The impact of HMG-CoA reductase inhibitors (statins) on cardiovascular mortality is well established. The pleotropic effects of statins extend beyond inhibition of cholesterol synthesis and the mevalonate pathway, including secondary prevention of prenylation and ubiquitination. Independent of the effect on HMG-CoA reductase, increasing evidence suggests that their lactone moiety may independently block the chymotrypsin activity of the proteasome. Proteosome inhibition results in the accumulation of p21 and p27 with subsequent inhibition of cyclin-dependent kinases and G₁ arrest. We investigated the impact of incidental statin use on patients with systemic Diffuse Large B Cell Lymphoma (DLBCL). Concurrently, we investigated the effect of statins on p27 expression in DLBCL.

We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital to identify all patients 18 years or older diagnosed with DLBCL between 2000 and 2006 (n=411). Patients were considered eligible for the study if they had a pathology-confirmed diagnosis of systemic DLBCL without evidence of a prior low grade lymphoma, received therapy with curative intent and had routine follow-up care within the system. 178 patients who did not meet these criteria were excluded. Final analysis included 233 patients who were evaluated for statin use via automated review of electronic medial records and billing databases (n=93 with statin use). Immunohistochemical staining for p27 was performed on six existing tissue samples. p27 IHC staining was performed manually using clone 57 (BD Biosciences) at a 1:100 dilution. Two control patient samples could not be assessed for p27 due to high background signal. Samples of two statin patients were compared to two control patients.

A total of 233 patients met eligibility and are included in the analysis. Median age was 60 years (range 19-92 years). 50% of patients were above 60 years of age, and 5% had an IPI score of 4 or higher. 74% of patients received CHOP + rituximab (RCHOP). 23% received CHOP alone. 3% recieved R-EPOCH and one received ProMACE-CytaBOM. At a median follow-up of 51 months (range 0-166 months), PFS and OS for the entire cohort are 72% and 77%, respectively. On univariate analysis of outcome, the incidental use of statins did not improve PFS (66.7% vs. 69.3%,p=0.955, Logrank Test) or OS (72.4% vs. 73.6%, p=0.456, Logrank Test).

In relapsed patients (n=30) statins prolonged disease free survival (DFS) (p=0.0515). Median DFS was 833 days for statin patients and 384 days for controls. Mean age of the relapsed patients on statins was 65 vs. 54 for controls. Tumor cells showed weak p27 staining in comparison to strong staining in background small lymphocytes in patients treated with statins, while patients not treated with statins showed no staining of tumor cells.

Incidental use of statins did not impact PFS or OS in DLBCL. Statins may slow disease progression in patients with relapsed DLBCL. One potential mechanism is upregulation of p27 and G1 cell cycle arrest.

Hochberg: Enzon: Consultancy, Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau.