Decitabine and Cedazuridine for Early Treatment of High-Risk Clonal Cytopenia of Undetermined Significance

Inclusion Criteria

• Age ≥ 18 years
• Unexplained cytopenia(s) for at least 4 months (at least two separate labs within 4 months including at time of screening must meet this criteria). Cytopenia(s) defined as 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 x 10^9/L ** Patients known to have a Duffy-null genotype must have anemia (Hgb < 12g/dL for women, Hgb < 13g/dL for men) and/or thrombocytopenia (platelet count [Plt] < 150 x 10^9/L) to be eligible for this study * Platelet count (Plt) < 150 x 10^9/L
• ≥ 1 pathogenic variant detected in any myeloid driver gene with a VAF of at least 0.02 (2%) identified by local next generation sequencing (NGS) of peripheral blood or bone marrow sample within 3 months from screening bone marrow biopsy
• Participants must have a high-risk score per the Clonal Hematopoiesis Risk Score (CHRS). Patients with a confirmed pathogenic variants in U2AF1 will be considered as having “high risk” mutations for the purposes of calculating the CHRS score
• Screening bone marrow biopsy must not be diagnostic of any overt hematologic malignancy by morphologic assessment and must be consistent with a diagnosis of clonal cytopenia of unknown significance (CCUS) as determined by multi-institutional hematopathology review. Multi-institutional review must be completed within the 42-day (6-week) screening window
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x upper limit of normal (ULN)
• Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be attributed 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-Gault glomerular filtration rate estimation
• Ability to understand and the willingness to sign a written informed consent document
• For participants of the early pharmacologic intervention cohort: women of childbearing potential must use highly effective contraception during treatment for at least 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose

Exclusion Criteria

• Concurrent primary malignancy requiring active cytotoxic chemotherapy and/or ionizing radiation therapy
• Known inherited bone marrow failure disorder and/or germline predisposition to hematologic malignancy
• Receipt of anti-cancer therapy including any cytotoxic chemotherapy, ionizing radiation therapy, immunomodulatory agents such as lenalidomide, and targeted anti-cancer therapies including poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors within the last 6 months. Patients with complete surgical resection of a tumor are not excluded from this study
• Anti-cancer therapy, including any cytotoxic chemotherapy, ionizing radiation therapy, immunomodulatory agents such as lenalidomide and targeted agents such as PARP inhibitors, planned in the next 6 months. Patients on hormonal adjuvant therapy for non-metastatic breast and prostate cancer or other minimally-myelosuppressive maintenance therapies for non-metastatic cancer may be eligible at the discretion of the study principal investigator (PI)
• Any prior diagnosis of MDS, myeloproliferative neoplasm (MPN), or chronic myelomonocytic leukemia (CMML) in the patient's lifetime, including individuals with previously identified MDS-defining chromosomal abnormalities identified by conventional karyotype or fluorescence in situ hybridization (FISH). In addition, patients cannot have previous diagnosis of acute myeloid leukemia (AML) or other hematolymphoid malignancy except in cases where the previous diagnosis was acute promyelocytic leukemia (APL or APML) or childhood acute lymphocytic leukemia (ALL) that is considered cured and not clonally related to present diagnosis of CCUS. Individuals with a remote history of other cured hematolymphoid malignancies may be considered for eligibility on a case-by-case basis at the PI's discretion
• Presence of a concurrent hematologic malignancy precursor state, such as smoldering multiple myeloma (SMM), and smoldering Waldenstrom’s macroglobulinemia
• Presence of a concurrent early-stage hematologic precursor state-such as monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B cell lymphocytosis (MBL)
• Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
• Recent (within 3 months) vaccination with any live attenuated vaccine or vaccination with live attenuated vaccine planned during the next 15 months * Live attenuated vaccines 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