This is a randomized, phase II, double-blind, placebo-controlled trial with planned crossover to the intervention arm after 1 year.

Consenting patients with CLL who have had at least one NMSC diagnosed in the past year will be randomized to receive either oral nicotinamide 500 mg twice daily (BID) for 1 year or oral placebo 1 tablet twice daily for 1 year. Patients will be stratified according to CLL therapy and the number of prior NMSC. At the end of 1 year, patients will undergo dermatologic examination and the number of new NMSC will be quantified. The number of patients who develop new NMSC in each arm will be documented. At this time, patients will be unblinded and all patients will receive Nicotinamide 500 mg BID for an additional year. At the end of this second year, patients will again undergo dermatologic examination, and the number of new NMSC will be quantified. The number of patients who develop NMSC will be documented. Skin biopsies will be taken for correlative studies.

Enrollment will be split into two parts separated by an interim analysis. Part 1 will accrue 40 patients: 20 to each arm. After 40 patients have completed their 12 month visit an interim futility analysis will be conducted prior to recruiting more patients. The study will stop if the difference in the number of patients with NMSC between control and treatment arms is 0 or less (i.e., absolutely no evidence that the treatment is better than control). If the trial is not stopped, the investigators will proceed with Part 2 and recruit 46 more patients.

Inclusion Criteria:

• Male or female subject aged ≥ 18 years.

• Confirmed diagnosis of CLL or small lymphocytic leukemia (SLL) per iwCLL 2018 criteria.

• History of ≥1 non-melanoma skin cancer (NMSC) diagnosed within the last 5 years

• Adequate liver function as defined as:

  • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

    ---Subjects with a known diagnosis of Gilbert's Syndrome: direct bilirubin ≤ 1.5x ULN

  • AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

• For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  --Women < 50 years of age:

  • Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
  • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
  • Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥ 50 years of age:

  • Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
  • Had radiation-induced menopause with last menses >1 year ago; or
  • Had chemotherapy-induced menopause with last menses >1 year ago; or
  • Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

• Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception.

Exclusion Criteria:

• Received cytotoxic chemotherapy (including fludarabine, cyclophosphamide, bendamustine, or chlorambucil) within the last 6 months
• Received allogeneic stem cell transplant within the last 6 months.
• Taking nicotinamide or niacin supplements within the last 4 weeks.
• Taken acitretin or other oral retinoids within the past 6 months
• Received field treatment for AKs (topical use of 5-fluorouracil, imiquimod, diclofenac, retinoids; topical photodynamic therapy for AKs; laser resurfacing or chemical peel treatments for AKs) within the previous 4 weeks
• Large areas of confluent skin cancer at baseline preventing accurate assessment and counting of individual new skin cancers
• Need for ongoing carbamazepine use (possible interaction with nicotinamide)
• Severe GI malabsorption that may interfere with absorption of nicotinamide (per investigator's discretion)
• Patients with an expected life expectancy < 2 years
• Current evidence of uncontrolled, diabetes.
• Current evidence or history of peptic ulcer disease.
• Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

• Known active uncontrolled infection.
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
• Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).
• Subjects taking prohibited medications as described in study protocol. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.
• Have ever received a solid organ transplant and are currently taking immunosuppressive medications.