Metformin is an antidiabetic drug which is an inexpensive and generally well tolerated medication. More recently metformin has been shown to act against carcinomas by two mechanisms: 1) an indirect, insulin-dependent mechanism which sensitizes tissues to insulin, inhibits hepatic gluconeogenesis, and stimulates uptake of glucose in muscle, thereby reducing fasting blood glucose and circulating levels of insulin, lowering the pro survival activity of the insulin/INSR axis, and 2) a direct, insulin-independent mechanism which activates the AMP-activated protein kinase (AMPK) pathway and leads to inhibition of the mTOR pathway. Given the investigators preliminary published data on insulin and mTOR inhibition[1] metformin is an attractive candidate for a pilot clinical trial in CLL patients.

Inclusion Criteria:

1. Patients should have a confirmed diagnosis of chronic lymphocytic leukemia defined as all of the following:

   • ALC > 5000
   • Positive for either CD19 or CD 20 together with CD23 and CD5.
   • Less than 55% atypical cells

2. Patients who relapse after receiving a one or more courses of fludarabine, bendamustine, cytoxan, rituxan, chlorambucil, or campath based therapy.

3. Patients should have findings of relapse by one or both of the following:

   • ALC > 5000 on 2 consecutive occasions and increasing
   • Any increase in lymphadenopathy over best response that has persisted for more than 3 months

4. Patient with confirmed del11q mutation may be included if untreated.

5. Age > or equal to 18 years old and < 80 years of age during the course of therapy

6. ECOG performance 0-2

7. Life expectancy > 12 months

8. Patients must have normal organ function as defined as below:

   • AST and ALT < 2 times the upper limit of normal
   • alkaline phosphatase < 2 ULN
   • serum conjugated bilirubin < 1.5 ULN (exception of Gilbert disease)
   • serum creatinine less than or equal to 1.5 in males, or 1.4 in females
   • GFR > 59

9. Ability to understand and the willingness to sign a written informed consent document

10. Patient must be able to drink and eat more than 75% of their usual daily meals.

Exclusion Criteria:

1. Patients with active CLL disease requiring urgent chemotherapy

2. Patients may not be receiving any other investigational agents.

3. Patients less than 30 days from last treatment for CLL.

4. History of allergic reactions attributed to metformin or other biguanides.

5. Known diabetes (type 1 or 2), fasting glucose > or equal to 7.0 mmol/L (126 mg/dL), or HgbA1C > 6.5

6. Currently taking metformin, sulfonylureas, thiazolidinediones or insulin for any reason

7. Current or planned pregnancy or lactation in women of child bearing age (confirmed by negative pregnancy test prior to start of therapy).

8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and sepsis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

9. Conditions which would increase risk of lactic acidosis including:

   • Known alcoholism or ingestion of more than 3 alcoholic beverages per day
   • History of congestive heart failure defined as NYHA class III or IV
   • History of metabolic acidosis
   • Ongoing or active infection concerning for sepsis or SIRS