This is an open-label, phase 2 study for lower risk MDS and high risk CCUS patients who are transfusion independent. There will be two cohorts enrolled at the same time to measure the effect of nicotinamide riboside and pterostilbene at different doses. The primary goals of the study are:

• to assess if study drug improves cytopenias in patients
• to determine safety of the study drug in patients

This is an open label, Phase 2 study for lower risk MDS and high risk CCUS patients who are transfusion independent.

Ten subjects will be accrued in this protocol in two cohorts. The first five subjects in cohort 1 will be given nicotinamide riboside and pterostilbene 250mg-50mg daily for a year. The second cohort will have five subjects and nicotinamide riboside and pterostilbene will be given 250mg-50mg twice daily for a year. The two cohorts can enroll concurrently. Study visits will be every 90 days. Two bone marrow biopsies will be performed, one at the time of screening and one after 180 days of therapy. The bone marrow biopsy at 180 days will serve to assess responses such as changes in variant allele frequencies, as well as correlative studies.

Inclusion Criteria:

• Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed procedures.

• Stated willingness to comply with all study procedures and be available for the duration of the study.

• Be a male or female aged ≥ 18 years of age.

• For persons of reproductive potential, use of highly effective method(s) of contraception.

• Subject must have confirmation of high risk CCUS (defined by CHRS score) or the diagnosis of MDS in the lower risk category as defined by IPSS-M less than 0.

• Patients must have ECOG of ≤ 2

• Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.

• Subject must have adequate liver function as demonstrated by:

  • aspartate aminotransferase (AST) ≤ 3.0 × ULN
  • alanine aminotransferase (ALT) ≤ 3.0 × ULN
  • Unless due to Gilbert's syndrome, patients must have a total bilirubin ≤ 3 × ULN.

• Subject is informed that consumption of the following fruits is prohibited 3 days prior to the initiation of study treatment and throughout participation: grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit.

Exclusion Criteria:

• Subject is known to be positive for HIV with uncontrolled disease. HIV testing is not required.

• Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV may participate.

• Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

  • Significant active cardiac disease within the previous 6 months including: New York Heart Association heart failure > class 2, unstable angina, or myocardial infarction.
  • Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.

• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. This includes history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease (e.g. sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.

• Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Uncontrolled is defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment.

• Subject has a history of other malignancies prior to study entry, with the exception of:

  • Adequately treated in situ carcinoma of the breast or cervix uteri
  • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
  • Prostate cancer not requiring therapy beyond hormonal therapy
  • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent

• Any subject who is transfusion dependent and a candidate for MDS therapy such as erythroid stimulating agents, thrombopoietin receptor agonists, Lusparercept, Imetelstat or hypomethylating agents.

• Pregnant or breast-feeding females. A pregnancy test will be obtained at the time of screening if applicable.

• Known or suspected hypersensitivity to nicotinamide riboside and pterostilbene.