Early Intervention in High Risk CCUS

Inclusion Criteria:

• Age ≥18 years.

• Unexplained cytopenia(s) for at least 4 months (at least two separate labs within 4months including at time of screening must meet this criteria). Cytopenia(s) definedas the presence of ≥ 1 of the following:

• Hemoglobin (Hgb) <12 g/dL for women and <13g/dL for men

• Absolute neutrophil count (ANC) < 1.8 × 109/L*

• Platelet count (Plt) <150 × 109/L *Patients known to have a Duffy-null genotypemust have anemia (Hgb < 12g/dL for women, Hgb <13g/dL for men) and/orthrombocytopenia (Plt < 150 × 109/L) to be eligible for this study.

• 1 pathogenic variant detected in any myeloid driver gene with a VAF of atleast 0.02 (2%) identified by local next generation sequencing (NGS) ofperipheral blood or bone marrow sample within 3 months from screening bonemarrow biopsy.

• Participants must have a high risk score per the Clonal Hematopoiesis RiskCalculator (CHRS). See APPENDIX C for calculation.

• Screening bone marrow biopsy must not be diagnostic of any overt hematologicmalignancy by morphologic assessment and must be consistent with a diagnosis ofclonal cytopenia of unknown significance (CCUS) as determined by multi-institutionalhematopathology review.

• ECOG performance status 0-2 (see Appendix A).

• Participants must meet the following organ function as defined below:

• Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤3x upper limit of normal (ULN).

• Serum total bilirubin <1.5x ULN. Higher levels are acceptable if these can beattributed to ineffective erythropoiesis or Gilbert's syndrome. In these cases,approval from the study Sponsor-Investigator is required.

• Creatinine clearance greater than 40 mL/min based on the Cockcroft-Gaultglomerular filtration rate estimation.

• Ability to understand and the willingness to sign a written informed consentdocument.

• For participants of the early pharmacologic intervention cohort: women ofchildbearing potential must use highly effective contraception during treatment forat least 6 months after the last dose and males with female partners of reproductivepotential should use effective contraception during treatment and for 3 months afterthe last dose.

Exclusion Criteria:

• Concurrent primary malignancy requiring active cytotoxic chemotherapy and/orionizing radiation therapy.

• Known inherited bone marrow failure disorder and/or germline predisposition tohematologic malignancy.

• Receipt of anti-cancer therapy including any cytotoxic chemotherapy, ionizingradiation therapy, immunomodulatory agents such as lenalidomide, and targetedanti-cancer therapies including PARP inhibitors within the last 6 months. Patientswith complete surgical resection of a tumor are not excluded from this study.

• Anti-cancer therapy, including any cytotoxic chemotherapy, ionizing radiationtherapy, immunomodulatory agents such as lenalidomide and targeted agents such asPARP inhibitors, planned in the next 6 months. Patients on hormonal adjuvant therapyfor nonmetastatic breast and prostate cancer or other minimally-myelosuppressivemaintenance therapies for non-metastatic cancer may be eligible at the discretion ofthe study PI.

• Diagnosis of MDS, MPN, CMML, AML or any other hematolymphoid malignancy in thepatient's lifetime. This includes individuals with MDS-defining chromosomalabnormalities identified via conventional karyotype or FISH.

• Presence of a concurrent hematologic malignancy precursor state, such as smolderingmultiple myeloma (SMM), and smoldering Waldenstrom's macroglobulinemia.

• Presence of an early-stage hematologic precursor state-such as monoclonal gammopathyof undetermined significance (MGUS) and monoclonal B cell lymphocytosis (MBL).

• Active uncontrolled systemic fungal, bacterial, or viral infection (defined asongoing signs/symptoms related to the infection without improvement despiteappropriate antibiotics, antiviral therapy, and/or other treatment).

• Recent (within 3 months) vaccination with any live attenuated vaccine or vaccinationwith live attenuated vaccine planned during the next 15 months. *Live attenuatedvaccines include measles, mumps, rubella (MMR combined vaccine), rotavirus,smallpox, chickenpox, and yellow fever.

• Laboratory evidence indicative of clinically significant red cell hemolysis.

• Hypersplenism and/or evidence of portal hypertension on physical exam or imaging.

• Pregnant or lactating.