Pyrimethamine for the Treatment of Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Inclusion Criteria: * Diagnosed with CLL/SLL based on the standard histologic and immunophenotypic criteria described in the WHO classification of lymphoid malignancies, including immunophenotypic confirmation that the tumor cells co-express B cell antigens CD19/20 and CD5. Mantle cell lymphoma should be excluded based on positive staining of the tumor cells for CD23, or the absence of staining of the tumor cells for cyclin D1 or the absence of t(11;14). This diagnosis should be confirmed at a Dana-Farber/Harvard Cancer Center institution within approximately one month after the subject is registered. * Measurable disease, defined as lymphocytosis \> 5,000/uL, or at least one palpable or CT measurable lesion \> approximately 1.5cm, or bone marrow involvement \> approximately 30% * Relapsed after at least one prior purine analogue-containing regimen, or at least two non-purine analogue containing regimens * 18 years of age or older * Life expectancy of greater than 3 months * ECOG performance status of 0, 1 or 2 * Normal organ function as outlined in the protocol * Require treatment based on IWCLL 2008 criteria * Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Exclusion Criteria: * Chemotherapy or radiotherapy within 3 weeks prior to entering the study or those who have not recovered from clinically significant adverse events due to agents administered more than 3 weeks earlier. * May not be receiving any other study agents * Known CNS involvement with CLL * History of allergic reactions or sensitivity to pyrimethamine * Patients taking folic acid are eligible if the folic acid is discontinued prior to pyrimethamine administration and not taken for the duration of time enrolled on this study * Prior allogeneic SCT is an exclusion only if the subject has active graft vs. host disease or requires immunosuppression other than a constant stable dose of glucocorticoids * Uncontrolled intercurrent illness * Pregnant or breastfeeding women * HIV-positive individuals on combination antiretroviral therapy