Therapeutic Effects of Metformin in Follicular Lymphoma (FL) Treated with Rituximab in Combination with Bendamustine

Introduction: Metformin is a frequently prescribed biguanide-class oral hypoglycemic agent. Clinically, it has been demonstrated that metformin improves outcomes when used alone or in combination with chemotherapy in diabetic cancer patients. Metformin derives its therapeutic effects from its intrinsic tumor-suppressor activity, specifically by a direct inhibitory effect in the adenosine monophosphate-activated protein kinase (AMPK) and target of the rapamycin (mTOR) pathways. Both signaling pathways had been targeted pharmacologically in B-cell malignancies. Previously, we demonstrated that the use of metformin during first line chemo-immunotherapy was associated with an improvement in progression free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL). The therapeutic effects of metformin in FL have not been studied. Methods: Using the RPCI tumor registry, we performed a retrospective cohort analysis to evaluate the effects of metformin on the clinical outcomes of FL patients who have received bendamustine and rituximab (BR) at our institute either in the front-line setting or in the relapsed/refractory (r/r) setting (N=80). Demographic, clinical, pharmacological and pathological characteristics were recorded. Differences in response rates (complete remission, partial remission and overall response rate), progression free survival (PFS) and overall survival (OS) were evaluated between non-diabetic pts, diabetic pts on metformin, and diabetic pts on other glucose-lowering agents. Results: Based on the use of metformin during chemo-immunotherapy, FL patients were classified as non-diabetic (N=60, 75%), diabetic on metformin (N=12, 15%) or diabetic on other glucose-lowering agents (N=8, 10%). The median age at diagnosis was 66yrs (34-97), 55% were female patients (N=44), 43.8% patients had a FLIPI score of 3 at diagnosis and 51.3% received at least 1 line of therapy. BR was given in the first line setting in 40 patients and in the relapsed/refractory setting in 41 patients (1 patient was treated with BR on two separate occasions during the course of his disease). The median OS for whole cohort of patients was 10 years (0-26y). Response rates to BR in both the first line setting and r/r settings were similar between metformin users and non-users. FL diabetic patients on metformin treated with BR in the first line setting had similar OS and PFS when compared to non-diabetic patients or diabetic patients on other glucose lowering agents (30mo vs 30mo for PFS) (80mo vs. 83 mo for OS). Conclusions: In this cohort analysis, metformin did not appear to provide a meaningful improvement in the response rates, PFS or OS when used during BR therapy for FL in the first line or r/r setting. The sample size and the heterogeneity of the patient population studied could have impacted our findings. Further pre-clinical studies and larger population cohort studies would better define the effect of metformin use in low grade B-cell lymphoma.